1
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Upadhyay S, Murugu L, Svensson L. Tumor cells escape immunosurveillance by hampering LFA-1. Front Immunol 2025; 16:1519841. [PMID: 39911389 PMCID: PMC11794523 DOI: 10.3389/fimmu.2025.1519841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 01/02/2025] [Indexed: 02/07/2025] Open
Abstract
During tumor immunosurveillance, leukocytes play a crucial role in the cellular defense system, working collaboratively with other immune components to recognize and eliminate aberrant cells. Integral to this process is the integrin Lymphocyte Function-Associated Antigen 1 (LFA-1). LFA-1 facilitates adhesion during leukocyte migration and helps establish stable cell-to-cell contacts between leukocytes and their targets. Additionally, as a receptor, LFA-1 signaling activates leukocytes, promoting their differentiation and effector functions against cancer. However, tumors can develop mechanisms to evade immune clearance by disrupting LFA-1 functions or hijacking its pathways. In this review, we first detail how leukocytes utilize LFA-1 during immunosurveillance and then explore how tumors counteract this process in the tumor microenvironment (TME) by either altering LFA-1 functions or exploiting it to drive tumorigenesis. Moreover, we discuss therapeutic strategies targeting LFA-1, including inhibitors tested in laboratory studies and animal models, highlighting their potential as anticancer interventions and the need for further research to evaluate their clinical utility.
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Affiliation(s)
| | - Lewis Murugu
- Department of Molecular Biology, Umeå University, Umeå, Sweden
| | - Lena Svensson
- Department of Molecular Biology, Umeå University, Umeå, Sweden
- Umeå Centre for Microbial Research, Umeå University, Umeå, Sweden
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2
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Arnaout MA. The Integrin Receptors: From Discovery to Structure to Medicines. Immunol Rev 2025; 329:e13433. [PMID: 39724488 PMCID: PMC11752789 DOI: 10.1111/imr.13433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 12/10/2024] [Indexed: 12/28/2024]
Abstract
Innate immune cells perform vital tasks in detecting, seeking, and eliminating invading pathogens, thus ensuring host survival. However, loss of function of these cells or their overactive response to tissue injury often causes serious ailments. It is, therefore, crucial to understand at a basic level how these cells function in health and disease. A major step toward this goal came from studies I conducted in the late 1970s investigating the cause of life-threatening bacterial infections in a pediatric patient. This work led us to trace this disease to the inability of the patient's neutrophils to seek and clear infections due to an inherited deficiency in leukocyte adhesion caused by the loss of a plasma membrane glycoprotein complex now known as CD11/CD18 or β2 integrins. I followed this work by determining the 3-dimensional structures of integrins. These studies provided the foundation for understanding the unique properties of integrins in mediating bidirectional cell adhesion signaling and enabled a structure-guided design of compounds to dial down overactive integrins in common disorders, including thromboinflammatory and autoimmune diseases.
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Affiliation(s)
- M Amin Arnaout
- Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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3
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Chattopadhyay S, Hazra R, Mallick A, Gayen S, Roy S. Small-molecule in cancer immunotherapy: Revolutionizing cancer treatment with transformative, game-changing breakthroughs. Biochim Biophys Acta Rev Cancer 2024; 1879:189170. [PMID: 39127244 DOI: 10.1016/j.bbcan.2024.189170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 08/05/2024] [Accepted: 08/06/2024] [Indexed: 08/12/2024]
Abstract
Immunotherapy has revolutionized cancer management, with antibody-based treatments leading the charge due to their superior pharmacodynamics, including enhanced effectiveness and specificity. However, these therapies are hampered by limitations such as prolonged half-lives, poor tissue and tumor penetration, and minimal oral bioavailability. Additionally, their immunogenic nature can cause adverse effects. Consequently, the focus is shifting towards small-molecule-based immunotherapies, which potentially overcome these drawbacks. Emerging as a promising alternative, small molecules offer the benefits of therapeutic antibodies and immunomodulators, often yielding synergistic effects when combined. Recent advancements in small-molecule cancer immunotherapy are notable, featuring inhibitors, agonists, and degraders that act as immunomodulators. This article delves into the current landscape of small-molecule immunotherapy in cancer treatment, highlighting novel agents targeting key pathways such as Toll-like receptors (TLR), PD-1/PD-L1, chemokine receptors, and stimulators of interferon genes (STING). The review emphasizes newly discovered molecular entities and their modulatory roles in tumorigenesis, many of which have progressed to clinical trials, that aims to provide a comprehensive snapshot of the evolving frontier in cancer treatment, driven by small-molecule immunomodulators.
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Affiliation(s)
- Soumyadeep Chattopadhyay
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India
| | - Rudradeep Hazra
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India
| | - Arijit Mallick
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India
| | - Sakuntala Gayen
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India
| | - Souvik Roy
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, West Bengal 700053, India.
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4
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Sapoznikov A, Kozlovski S, Levi N, Feigelson SW, Regev O, Davidzohn N, Ben-Dor S, Haffner-Krausz R, Feldmesser E, Wigoda N, Petrovich-Kopitman E, Biton M, Alon R. Dendritic cell ICAM-1 strengthens synapses with CD8 T cells but is not required for their early differentiation. Cell Rep 2023; 42:112864. [PMID: 37494182 DOI: 10.1016/j.celrep.2023.112864] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 06/13/2023] [Accepted: 07/10/2023] [Indexed: 07/28/2023] Open
Abstract
Lymphocyte priming in lymph nodes (LNs) was postulated to depend on the formation of stable T cell receptor (TCR)-specific immune synapses (ISs) with antigen (Ag)-presenting dendritic cells (DCs). The high-affinity LFA-1 ligand ICAM-1 was implicated in different ISs studied in vitro. We dissect the in vivo roles of endogenous DC ICAM-1 in Ag-stimulated T cell proliferation and differentiation and find that under type 1 polarizing conditions in vaccinated or vaccinia virus-infected skin-draining LNs, Ag-presenting DCs engage in ICAM-1-dependent stable conjugates with a subset of Ag-specific CD8 blasts. Nevertheless, in the absence of these conjugates, CD8 lymphocyte proliferation and differentiation into functional cytotoxic T cells (CTLs) and skin homing effector lymphocytes takes place normally. Our results suggest that although CD8 T cell blasts engage in tight ICAM-1-dependent DC-T ISs, firm ISs are dispensable for TCR-triggered proliferation and differentiation into productive effector lymphocytes.
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Affiliation(s)
- Anita Sapoznikov
- Deptartment of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Stav Kozlovski
- Deptartment of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Nehora Levi
- Deptartment of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Sara W Feigelson
- Deptartment of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Ofer Regev
- Deptartment of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Natalia Davidzohn
- Deptartment of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Shifra Ben-Dor
- Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | | | - Ester Feldmesser
- Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | - Noa Wigoda
- Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | | | - Moshe Biton
- Deptartment of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel.
| | - Ronen Alon
- Deptartment of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel.
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5
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Guo J, Xu Z, Gunderson RC, Xu B, Michie SA. LFA-1/ICAM-1 Adhesion Pathway Mediates the Homeostatic Migration of Lymphocytes from Peripheral Tissues into Lymph Nodes through Lymphatic Vessels. Biomolecules 2023; 13:1194. [PMID: 37627259 PMCID: PMC10452152 DOI: 10.3390/biom13081194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 07/22/2023] [Accepted: 07/29/2023] [Indexed: 08/27/2023] Open
Abstract
Lymphocyte function-associated antigen-1 (LFA-1) and its endothelial ligand intercellular adhesion molecule-1 (ICAM-1) are important for the migration of lymphocytes from blood vessels into lymph nodes. However, it is largely unknown whether these molecules mediate the homeostatic migration of lymphocytes from peripheral tissues into lymph nodes through lymphatic vessels. In this study, we find that, in naive mice, ICAM-1 is expressed on the sinus endothelia of lymph nodes, but not on the lymphatic vessels of peripheral tissues. In in vivo lymphocyte migration assays, memory CD4+ T cells migrated to lymph nodes from peripheral tissues much more efficiently than from blood vessels, as compared to naive CD4+ T cells. Moreover, ICAM-1 deficiency in host mice significantly inhibited the migration of adoptively transferred wild-type donor lymphocytes from peripheral tissues, but not from blood vessels, into lymph nodes. The migration of LFA-1-deficient donor lymphocytes from peripheral tissues into the lymph nodes of wild-type host mice was also significantly reduced as compared to wild-type donor lymphocytes. Furthermore, the number of memory T cells in lymph nodes was significantly reduced in the absence of ICAM-1 or LFA-1. Thus, our study extends the functions of the LFA-1/ICAM-1 adhesion pathway, indicating its novel role in controlling the homeostatic migration of lymphocytes from peripheral tissues into lymph nodes and maintaining memory T cellularity in lymph nodes.
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Affiliation(s)
- Jia Guo
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; (J.G.); (Z.X.); (R.C.G.)
- Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
- Center for Hypertension Care, Shanxi Medical University First Hospital, Taiyuan 030012, China
| | - Zeyu Xu
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; (J.G.); (Z.X.); (R.C.G.)
- Department of Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45219, USA
| | - Rachel C. Gunderson
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; (J.G.); (Z.X.); (R.C.G.)
| | - Baohui Xu
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; (J.G.); (Z.X.); (R.C.G.)
- Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Sara A. Michie
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; (J.G.); (Z.X.); (R.C.G.)
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6
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Li GQ, Xia J, Zeng W, Luo W, Liu L, Zeng X, Cao D. The intestinal γδ T cells: functions in the gut and in the distant organs. Front Immunol 2023; 14:1206299. [PMID: 37398661 PMCID: PMC10311558 DOI: 10.3389/fimmu.2023.1206299] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 06/05/2023] [Indexed: 07/04/2023] Open
Abstract
Located in the frontline against the largest population of microbiota, the intestinal mucosa of mammals has evolved to become an effective immune system. γδ T cells, a unique T cell subpopulation, are rare in circulation blood and lymphoid tissues, but rich in the intestinal mucosa, particularly in the epithelium. Via rapid production of cytokines and growth factors, intestinal γδ T cells are key contributors to epithelial homeostasis and immune surveillance of infection. Intriguingly, recent studies have revealed that the intestinal γδ T cells may play novel exciting functions ranging from epithelial plasticity and remodeling in response to carbohydrate diets to the recovery of ischemic stroke. In this review article, we update regulatory molecules newly defined in lymphopoiesis of the intestinal γδ T cells and their novel functions locally in the intestinal mucosa, such as epithelial remodeling, and distantly in pathological setting, e.g., ischemic brain injury repair, psychosocial stress responses, and fracture repair. The challenges and potential revenues in intestinal γδ T cell studies are discussed.
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Affiliation(s)
- Guo-Qing Li
- Department of Gastroenterology, Clinical Research Center, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research on Gastrointestinal Tumors, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Jiliang Xia
- Hunan Province Key Laboratory of Cancer Cellular and Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Weihong Zeng
- Hunan Province Key Laboratory of Cancer Cellular and Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Weijia Luo
- Hunan Province Key Laboratory of Cancer Cellular and Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Logen Liu
- Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research on Gastrointestinal Tumors, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Xi Zeng
- Hunan Province Key Laboratory of Cancer Cellular and Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Deliang Cao
- Department of Gastroenterology, Clinical Research Center, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- Hunan Province Key Laboratory of Cancer Cellular and Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- Department of Oncology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
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7
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Patras L, Shaashua L, Matei I, Lyden D. Immune determinants of the pre-metastatic niche. Cancer Cell 2023; 41:546-572. [PMID: 36917952 PMCID: PMC10170403 DOI: 10.1016/j.ccell.2023.02.018] [Citation(s) in RCA: 85] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 02/11/2023] [Accepted: 02/13/2023] [Indexed: 03/16/2023]
Abstract
Primary tumors actively and specifically prime pre-metastatic niches (PMNs), the future sites of organotropic metastasis, preparing these distant microenvironments for disseminated tumor cell arrival. While initial studies of the PMN focused on extracellular matrix alterations and stromal reprogramming, it is increasingly clear that the far-reaching effects of tumors are in great part achieved through systemic and local PMN immunosuppression. Here, we discuss recent advances in our understanding of the tumor immune microenvironment and provide a comprehensive overview of the immune determinants of the PMN's spatiotemporal evolution. Moreover, we depict the PMN immune landscape, based on functional pre-clinical studies as well as mounting clinical evidence, and the dynamic, reciprocal crosstalk with systemic changes imposed by cancer progression. Finally, we outline emerging therapeutic approaches that alter the dynamics of the interactions driving PMN formation and reverse immunosuppression programs in the PMN ensuring early anti-tumor immune responses.
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Affiliation(s)
- Laura Patras
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Department of Molecular Biology and Biotechnology, Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, Babes-Bolyai University, Cluj-Napoca, Romania
| | - Lee Shaashua
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Irina Matei
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
| | - David Lyden
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
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8
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Yahyazadeh R, Baradaran Rahimi V, Mohajeri SA, Iranshahy M, Yahyazadeh A, Hasanpour M, Iranshahi M, Askari VR. Oral Administration Evaluation of the Hydro-Ethanolic Extract of Ginger (Rhizome of Zingiber officinale) against Postoperative-Induced Peritoneal Adhesion: Investigating the Role of Anti-Inflammatory and Antioxidative Effects. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2023; 2023:4086631. [PMID: 36865747 PMCID: PMC9974257 DOI: 10.1155/2023/4086631] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 10/10/2022] [Accepted: 02/02/2023] [Indexed: 02/25/2023]
Abstract
Peritoneal adhesions (PAs) occur and develop after abdominal surgery. Abdominal adhesions are common and often develop after abdominal surgery. Currently, there are no effective targeted pharmacotherapies for treating adhesive disease. In this regard, ginger is wildly used in traditional medicine because of its anti-inflammatory and antioxidant effects and has been investigated for peritoneal adhesion treatment. This study analyzed ginger ethanolic extraction via HPLC to have a 6-gingerol concentration. Four groups induced peritoneal adhesion to evaluate ginger's effects on peritoneal adhesion. Then, ginger extract (50, 150, and 450 mg/kg) was administered by gavage in various groups of male Wistar rats (220 ± 20 g, 6-8 weeks). After scarifying the animals for biological assessment, macroscopic and microscopic parameters were determined via scoring systems and immunoassays in the peritoneal lavage fluid. Next, the adhesion scores and interleukin IL-6, IL-10, tumor necrosis factor-(TNF-) α, transforming growth factor-(TGF-) β1, vascular endothelial growth factor (VEGF), and malondialdehyde (MDA) were elevated in the control group. The results showed that ginger extract (450 mg/kg) notably decreased inflammatory (IL-6 and TNF-α), fibrosis (TGF-β1), anti-inflammatory cytokine (IL-10), angiogenesis (VEGF), and oxidative (MDA) factors, while increased antioxidant factor glutathione (GSH), compared to the control group. These findings suggest that a hydro-alcoholic extract of ginger is a potentially novel therapeutic strategy for inhibiting adhesion formation. Also, it might be considered a beneficial anti-inflammatory or antifibrosis herbal medicine in clinical trials. However, further clinical studies are required to approve the effectiveness of ginger.
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Affiliation(s)
- Roghayeh Yahyazadeh
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vafa Baradaran Rahimi
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Cardiovascular Diseases, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Ahmad Mohajeri
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Milad Iranshahy
- Department of Pharmacognosy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ahmad Yahyazadeh
- Department of Histology and Embryology, Faculty of Medicine, Karabuk University, Karabuk, Turkey
| | - Maede Hasanpour
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehrdad Iranshahi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vahid Reza Askari
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
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9
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Klaus T, Wilson AS, Vicari E, Hadaschik E, Klein M, Helbich SSC, Kamenjarin N, Hodapp K, Schunke J, Haist M, Butsch F, Probst HC, Enk AH, Mahnke K, Waisman A, Bednarczyk M, Bros M, Bopp T, Grabbe S. Impaired Treg-DC interactions contribute to autoimmunity in leukocyte adhesion deficiency type 1. JCI Insight 2022; 7:162580. [PMID: 36346673 PMCID: PMC9869970 DOI: 10.1172/jci.insight.162580] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 11/04/2022] [Indexed: 11/09/2022] Open
Abstract
Leukocyte adhesion deficiency type 1 (LAD-1) is a rare disease resulting from mutations in the gene encoding for the common β-chain of the β2-integrin family (CD18). The most prominent clinical symptoms are profound leukocytosis and high susceptibility to infections. Patients with LAD-1 are prone to develop autoimmune diseases, but the molecular and cellular mechanisms that result in coexisting immunodeficiency and autoimmunity are still unresolved. CD4+FOXP3+ Treg are known for their essential role in preventing autoimmunity. To understand the role of Treg in LAD-1 development and manifestation of autoimmunity, we generated mice specifically lacking CD18 on Treg (CD18Foxp3), resulting in defective LFA-1 expression. Here, we demonstrate a crucial role of LFA-1 on Treg to maintain immune homeostasis by modifying T cell-DC interactions and CD4+ T cell activation. Treg-specific CD18 deletion did not impair Treg migration into extralymphatic organs, but it resulted in shorter interactions of Treg with DC. In vivo, CD18Foxp3 mice developed spontaneous hyperplasia in lymphatic organs and diffuse inflammation of the skin and in multiple internal organs. Thus, LFA-1 on Treg is required for the maintenance of immune homeostasis.
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Affiliation(s)
- Tanja Klaus
- Department of Dermatology,,Research Center for Immunotherapy, and
| | - Alicia S. Wilson
- Research Center for Immunotherapy, and,Institute of Immunology, University of Mainz Medical Center, Mainz, Germany
| | - Elisabeth Vicari
- Department of Dermatology, University of Heidelberg, Heidelberg, Germany
| | - Eva Hadaschik
- Department of Dermatology, University of Heidelberg, Heidelberg, Germany.,Department of Dermatology, University Hospital Essen, Essen, Germany
| | - Matthias Klein
- Research Center for Immunotherapy, and,Institute of Immunology, University of Mainz Medical Center, Mainz, Germany
| | | | - Nadine Kamenjarin
- Research Center for Immunotherapy, and,Institute of Immunology, University of Mainz Medical Center, Mainz, Germany
| | - Katrin Hodapp
- Research Center for Immunotherapy, and,Institute of Immunology, University of Mainz Medical Center, Mainz, Germany
| | - Jenny Schunke
- Department of Dermatology,,Research Center for Immunotherapy, and
| | - Maximilian Haist
- Department of Dermatology,,Research Center for Immunotherapy, and
| | | | - Hans Christian Probst
- Research Center for Immunotherapy, and,Institute of Immunology, University of Mainz Medical Center, Mainz, Germany
| | - Alexander H. Enk
- Department of Dermatology, University of Heidelberg, Heidelberg, Germany
| | - Karsten Mahnke
- Department of Dermatology, University of Heidelberg, Heidelberg, Germany
| | - Ari Waisman
- Research Center for Immunotherapy, and,Institute for Molecular Medicine, University of Mainz Medical Center, Mainz, Germany
| | | | - Matthias Bros
- Department of Dermatology,,Research Center for Immunotherapy, and
| | - Tobias Bopp
- Research Center for Immunotherapy, and,Institute of Immunology, University of Mainz Medical Center, Mainz, Germany
| | - Stephan Grabbe
- Department of Dermatology,,Research Center for Immunotherapy, and
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10
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Ndinyanka Fabrice T, Bianda C, Zhang H, Jayachandran R, Ruer-Laventie J, Mori M, Moshous D, Fucile G, Schmidt A, Pieters J. An evolutionarily conserved coronin-dependent pathway defines cell population size. Sci Signal 2022; 15:eabo5363. [DOI: 10.1126/scisignal.abo5363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Maintenance of cell population size is fundamental to the proper functioning of multicellular organisms. Here, we describe a cell-intrinsic cell density–sensing pathway that enabled T cells to reach and maintain an appropriate population size. This pathway operated “kin-to-kin” or between identical or similar T cell populations occupying a niche within a tissue or organ, such as the lymph nodes, spleen, and blood. We showed that this pathway depended on the cell density–dependent abundance of the evolutionarily conserved protein coronin 1, which coordinated prosurvival signaling with the inhibition of cell death until the cell population reached threshold densities. At or above threshold densities, coronin 1 expression peaked and remained stable, thereby resulting in the initiation of apoptosis through kin-to-kin intercellular signaling to return the cell population to the appropriate cell density. This cell population size-controlling pathway was conserved from amoeba to humans, thus providing evidence for the existence of a coronin-regulated, evolutionarily conserved mechanism by which cells are informed of and coordinate their relative population size.
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Affiliation(s)
| | | | - Haiyan Zhang
- Biozentrum, University of Basel, 4056 Basel, Switzerland
| | | | | | - Mayumi Mori
- Biozentrum, University of Basel, 4056 Basel, Switzerland
| | - Despina Moshous
- Pediatric Immunology, Hematology and Rheumatology Unit, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris and Imagine Institute, INSERM UMR1163, Université de Paris, 75015 Paris, France
| | - Geoffrey Fucile
- SIB Swiss Institute of Bioinformatics, sciCORE Computing Center, University of Basel, 4056 Basel, Switzerland
| | | | - Jean Pieters
- Biozentrum, University of Basel, 4056 Basel, Switzerland
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11
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Serum levels of IgM to phosphatidylcholine predict the response of multiple sclerosis patients to natalizumab or IFN-β. Sci Rep 2022; 12:13357. [PMID: 35922641 PMCID: PMC9349316 DOI: 10.1038/s41598-022-16218-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 07/06/2022] [Indexed: 11/09/2022] Open
Abstract
We developed an ELISA assay demonstrating the high prevalence of serum IgM to phosphatidylcholine (IgM-PC) in the first stages of multiple sclerosis (MS). We aimed to analyze the role of serum IgM-PC as a biomarker of response to treatment. Paired serum samples from 95 MS patients were obtained before (b.t) and after (a.t) treatment with disease modifying therapies. Patients were classified as non-responders or responders to treatment, according to classical criteria. Serum IgM-PC concentration was analyzed using our house ELISA assay. The level of serum IgM-PC b.t was higher in patients treated later with natalizumab than in those treated with Copaxone (p = 0.011) or interferon-β (p = 0.009). Responders to natalizumab showed higher concentration of serum IgM-PC b.t than those who did not respond to it (p = 0.019). The 73.3% of patients with the highest level of serum IgM-PC b.t responded to natalizumab. IgM-PC level decreased a.t in both cases, non-responders and responders to natalizumab. IgM-PC levels a.t did not decrease in non-responders to interferon-β, but in responders to it the IgM-PC level decreased (p = 0.007). Serum IgM-PC could be a biomarker of response to natalizumab or interferon-β treatment. Further studies would be necessary to validate these results.
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12
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Reed SG, Ager A. Immune Responses to IAV Infection and the Roles of L-Selectin and ADAM17 in Lymphocyte Homing. Pathogens 2022; 11:pathogens11020150. [PMID: 35215094 PMCID: PMC8878872 DOI: 10.3390/pathogens11020150] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 01/14/2022] [Accepted: 01/21/2022] [Indexed: 02/04/2023] Open
Abstract
Influenza A virus (IAV) infection is a global public health burden causing up to 650,000 deaths per year. Yearly vaccination programmes and anti-viral drugs currently have limited benefits; therefore, research into IAV is fundamental. Leukocyte trafficking is a crucial process which orchestrates the immune response to infection to protect the host. It involves several homing molecules and receptors on both blood vessels and leukocytes. A key mediator of this process is the transmembrane glycoprotein L-selectin, which binds to vascular addressins on blood vessel endothelial cells. L-selectin classically mediates homing of naïve and central memory lymphocytes to lymph nodes via high endothelial venules (HEVs). Recent studies have found that L-selectin is essential for homing of activated CD8+ T cells to influenza-infected lungs and reduction in virus load. A disintegrin and metalloproteinase 17 (ADAM17) is the primary regulator of cell surface levels of L-selectin. Understanding the mechanisms that regulate these two proteins are central to comprehending recruitment of T cells to sites of IAV infection. This review summarises the immune response to IAV infection in humans and mice and discusses the roles of L-selectin and ADAM17 in T lymphocyte homing during IAV infection.
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Affiliation(s)
| | - Ann Ager
- Correspondence: (S.G.R.); (A.A.)
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13
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Czaja AJ. Review article: targeting the B cell activation system in autoimmune hepatitis. Aliment Pharmacol Ther 2021; 54:902-922. [PMID: 34506662 DOI: 10.1111/apt.16574] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/30/2021] [Accepted: 08/05/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND The B cell activation system, consisting of B cell activating factor and a proliferation-inducing ligand, may have pathogenic effects in autoimmune hepatitis. AIMS To describe the biological actions of the B cell activation system, indicate its possible role in autoimmune diseases, and evaluate its prospects as a therapeutic target in autoimmune hepatitis METHODS: English abstracts were identified in PubMed by multiple search terms. Full length articles were selected for review, and secondary and tertiary bibliographies were developed. RESULTS The B cell activating factor is crucial for the maturation and survival of B cells, and it can co-stimulate T cell activation, proliferation, and survival. It can also modulate the immune response by inducing interleukin 10 production by regulatory B cells. A proliferation-inducing ligand modulates and diversifies the antibody response by inducing class-switch recombination in B cells. It can also increase the proliferation, survival, and antigen activation of T cells. These immune stimulatory actions can be modulated by inducing proliferation of regulatory T cells. The B cell activation system has been implicated in diverse autoimmune diseases, and therapeutic blockade is a management strategy now being evaluated in autoimmune hepatitis. CONCLUSIONS The B cell activation system has profound effects on B and T cell function in autoimmune diseases. Blockade therapy is being actively evaluated in autoimmune hepatitis. Clarification of the critical pathogenic components of the B cell activation system will improve the targeting, efficacy, and safety of blockade therapy in this disease.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
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14
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Castillo-Ramírez DA, Carrasco-Yépez MM, Rodríguez-Mera IB, Reséndiz-Albor AA, Rosales-Cruz É, Rojas-Hernández S. A 250-kDa glycoprotein of Naegleria fowleri induces protection and modifies the expression of α4β1 and LFA-1 on T and B lymphocytes in mouse meningitis model. Parasite Immunol 2021; 43:e12882. [PMID: 34570374 DOI: 10.1111/pim.12882] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 09/10/2021] [Accepted: 09/20/2021] [Indexed: 11/29/2022]
Abstract
The aims of this work were to evaluate the protective role of the 250-kDa polypeptide band of Naegleria fowleri. We designed an immunization strategy in Balb/c mice which were inoculated by i.n. route with an electrocuted 250-kDa polypeptide band of N. fowleri. We observed that the 250-kDa band induced 80% of protection, whereas the coadministration with Cholera Toxin induced 100% of protection. Moreover, high levels of IgA- and IgG-specific antibodies were detected by ELISA assay. We also analysed migration molecules (α4β1 and LFA-1) on T and B lymphocytes in nose-associated lymphoid tissue (NALT), cervical lymph nodes (CN) and nasal passages (NP) by flow cytometry. We observed that the percentage of B cells (B220/α4β1) and T cells (CD4/α4β1) in NP were higher in all immunized groups compared with the other compartments analysed. Finally, we detected by immunohistochemistry ICAM-1 and V-CAM-1 in the nasal cavity. The immunization with the 250-kDa polypeptide band, protect mice against N. fowleri challenge and modifies migration molecules and their ligands.
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Affiliation(s)
- Diego A Castillo-Ramírez
- Instituto Politécnico Nacional, Salvador Díaz Mirón esq. Plan de San Luis S/N, Miguel Hidalgo, Casco de Santo Tomas, Escuela Superior de Medicina, Ciudad de México, México
| | - María Maricela Carrasco-Yépez
- Laboratorio de Microbiología Ambiental, Grupo CyMA, UIICSE, FES Iztacala, UNAM, Estado de México, Tlalnepantla de Baz, México
| | - Itzel Berenice Rodríguez-Mera
- Instituto Politécnico Nacional, Salvador Díaz Mirón esq. Plan de San Luis S/N, Miguel Hidalgo, Casco de Santo Tomas, Escuela Superior de Medicina, Ciudad de México, México
| | - Aldo Arturo Reséndiz-Albor
- Instituto Politécnico Nacional, Salvador Díaz Mirón esq. Plan de San Luis S/N, Miguel Hidalgo, Casco de Santo Tomas, Escuela Superior de Medicina, Ciudad de México, México
| | - Érica Rosales-Cruz
- Laboratorio de Investigación en Hematopatología, Departamento de Morfología, Escuela Nacional de Ciencias Biológicas, México City, México
| | - Saúl Rojas-Hernández
- Instituto Politécnico Nacional, Salvador Díaz Mirón esq. Plan de San Luis S/N, Miguel Hidalgo, Casco de Santo Tomas, Escuela Superior de Medicina, Ciudad de México, México
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15
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Johansen KH, Golec DP, Thomsen JH, Schwartzberg PL, Okkenhaug K. PI3K in T Cell Adhesion and Trafficking. Front Immunol 2021; 12:708908. [PMID: 34421914 PMCID: PMC8377255 DOI: 10.3389/fimmu.2021.708908] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 07/19/2021] [Indexed: 12/12/2022] Open
Abstract
PI3K signalling is required for activation, differentiation, and trafficking of T cells. PI3Kδ, the dominant PI3K isoform in T cells, has been extensively characterised using PI3Kδ mutant mouse models and PI3K inhibitors. Furthermore, characterisation of patients with Activated PI3K Delta Syndrome (APDS) and mouse models with hyperactive PI3Kδ have shed light on how increased PI3Kδ activity affects T cell functions. An important function of PI3Kδ is that it acts downstream of TCR stimulation to activate the major T cell integrin, LFA-1, which controls transendothelial migration of T cells as well as their interaction with antigen-presenting cells. PI3Kδ also suppresses the cell surface expression of CD62L and CCR7 which controls the migration of T cells across high endothelial venules in the lymph nodes and S1PR1 which controls lymph node egress. Therefore, PI3Kδ can control both entry and exit of T cells from lymph nodes as well as the recruitment to and retention of T cells within inflamed tissues. This review will focus on the regulation of adhesion receptors by PI3Kδ and how this contributes to T cell trafficking and localisation. These findings are relevant for our understanding of how PI3Kδ inhibitors may affect T cell redistribution and function.
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Affiliation(s)
- Kristoffer H Johansen
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom.,Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, United States
| | - Dominic P Golec
- Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, United States
| | - Julie H Thomsen
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
| | | | - Klaus Okkenhaug
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
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16
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Nosenko MA, Moysenovich AM, Arkhipova AY, Atretkhany KSN, Nedospasov SA, Drutskaya MS, Moisenovich MM. Fibroblasts upregulate expression of adhesion molecules and promote lymphocyte retention in 3D fibroin/gelatin scaffolds. Bioact Mater 2021; 6:3449-3460. [PMID: 33817420 PMCID: PMC7988350 DOI: 10.1016/j.bioactmat.2021.03.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 02/05/2021] [Accepted: 03/04/2021] [Indexed: 01/16/2023] Open
Abstract
Bioengineered scaffolds are crucial components in artificial tissue construction. In general, these scaffolds provide inert three-dimensional (3D) surfaces supporting cell growth. However, some scaffolds can affect the phenotype of cultured cells, especially, adherent stromal cells, such as fibroblasts. Here we report on unique properties of 3D fibroin/gelatin materials, which may rapidly induce expression of adhesion molecules, such as ICAM-1 and VCAM-1, in cultured primary murine embryonic fibroblasts (MEFs). In contrast, two-dimensional (2D) fibroin/gelatin films did not show significant effects on gene expression profiles in fibroblasts as compared to 3D culture conditions. Interestingly, TNF expression was induced in MEFs cultured in 3D fibroin/gelatin scaffolds, while genetic or pharmacological TNF ablation resulted in diminished ICAM-1 and VCAM-1 expression by these cells. Using selective MAPK inhibitors, we uncovered critical contribution of JNK to 3D-induced upregulation of these adhesion molecules. Moreover, we observed ICAM-1/VCAM-1-dependent adhesion of lymphocytes to fibroblasts cultured in 3D fibroin/gelatin scaffolds, but not on 2D fibroin/gelatin films, suggesting functional reprogramming in stromal cells, when exposed to 3D environment. Finally, we observed significant infiltration of lymphocytes into 3D fibroin/gelatin, but not into collagen scaffolds in vivo upon subcapsular kidney implantation in mice. Together our data highlight the important features of fibroin/gelatin scaffolds, when they are produced as 3D sponges rather than 2D films, which should be considered when using these materials for tissue engineering.
3D, but not 2D fibroin-based scaffolds promote expression of adhesion molecules in murine fibroblasts. Overexpression of adhesion molecules in 3D fibroin/gelatin-cultured fibroblasts is TNF- and JNK-dependent. Culturing of fibroblasts in 3D fibroin/gelatin scaffolds promotes adhesion of T-lymphocytes. Implantation of 3D fibroin/gelatin scaffolds in vivo induces infiltration and clustering of T- and B-lymphocytes.
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Affiliation(s)
- Maxim A Nosenko
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia
| | | | - Anastasia Y Arkhipova
- Biological Faculty, Lomonosov Moscow State University, Moscow, 119991, Russia.,Biological Faculty, Shenzhen MSU-BIT University, Shenzhen, 518172, China
| | - Kamar-Sulu N Atretkhany
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia
| | - Sergei A Nedospasov
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia.,Biological Faculty, Lomonosov Moscow State University, Moscow, 119991, Russia.,Sirius University of Science and Technology, Federal Territory Sirius, Krasnodarsky Krai, 354340, Russia
| | - Marina S Drutskaya
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia
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17
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Saveliev A, Bell SE, Turner M. Efficient homing of antibody-secreting cells to the bone marrow requires RNA-binding protein ZFP36L1. J Exp Med 2021; 218:e20200504. [PMID: 33306108 PMCID: PMC7744253 DOI: 10.1084/jem.20200504] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 05/16/2020] [Accepted: 10/29/2020] [Indexed: 12/19/2022] Open
Abstract
Cell migration relies on coordinated activity of chemotactic and guidance receptors. Here, we report a specific role for the RNA-binding protein ZFP36L1 in limiting the abundance of molecules involved in the homing of antibody-secreting cells (ASCs) to the bone marrow (BM). In the absence of ZFP36L1, ASCs build up in the spleen and the liver and show diminished accumulation in the BM. ZFP36L1 facilitates migration by directly regulating G protein-coupled receptor kinase 2 (GRK2) and the integrin chains α4 and β1 in splenic ASCs. Expression of CXCR4 and of the integrins α4 and β1 is differentially regulated on ASCs produced at the early and late stages of the immune response. Consequently, deletion of the Zfp36l1 gene has a stronger effect on BM accumulation of high-affinity ASCs formed late in the response. Thus, ZFP36L1 is an integral part of the regulatory network controlling gene expression during ASC homing.
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Affiliation(s)
- Alexander Saveliev
- Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, UK
| | - Sarah E Bell
- Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, UK
| | - Martin Turner
- Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, UK
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18
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Cho EA, Zhang P, Kumar V, Kavalchuk M, Zhang H, Huang Q, Duncan JS, Wu J. Phosphorylation of RIAM by src promotes integrin activation by unmasking the PH domain of RIAM. Structure 2020; 29:320-329.e4. [PMID: 33275877 DOI: 10.1016/j.str.2020.11.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 10/12/2020] [Accepted: 11/13/2020] [Indexed: 02/07/2023]
Abstract
Integrin activation controls cell adhesion, migration, invasion, and extracellular matrix remodeling. RIAM (RAP1-GTP-interacting adaptor molecule) is recruited by activated RAP1 to the plasma membrane (PM) to mediate integrin activation via an inside-out signaling pathway. This process requires the association of the pleckstrin homology (PH) domain of RIAM with the membrane PIP2. We identify a conserved intermolecular interface that masks the PIP2-binding site in the PH domains of RIAM. Our data indicate that phosphorylation of RIAM by Src family kinases disrupts this PH-mediated interface, unmasks the membrane PIP2-binding site, and promotes integrin activation. We further demonstrate that this process requires phosphorylation of Tyr267 and Tyr427 in the RIAM PH domain by Src. Our data reveal an unorthodox regulatory mechanism of small GTPase effector proteins by phosphorylation-dependent PM association of the PH domain and provide new insights into the link between Src kinases and integrin signaling.
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Affiliation(s)
- Eun-Ah Cho
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Pingfeng Zhang
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Vikas Kumar
- Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Mikhail Kavalchuk
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Hao Zhang
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | | | - James S Duncan
- Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Jinhua Wu
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
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19
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Perro M, Iannacone M, von Andrian UH, Peixoto A. Role of LFA-1 integrin in the control of a lymphocytic choriomeningitis virus (LCMV) infection. Virulence 2020; 11:1640-1655. [PMID: 33251934 PMCID: PMC7714442 DOI: 10.1080/21505594.2020.1845506] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Leukocyte function-associated antigen 1 (LFA-1) is the most widely expressed member of the β2 integrin family of cell-cell adhesion molecules. Although LFA-1 is thought to regulate multiple aspects of T cell immunity, its role in the response of CD8+ T cells to viral infections remains unclear. Indeed, compelling clinical evidence shows that loss of LFA-1 function predisposes to infection in humans but animal models show limited to no susceptibility to infection. Here, we addressed this conundrum in a mouse model of infection with lymphocytic choriomeningitis virus (LCMV), where CD8+ T cells are necessary and sufficient to confer protection. To this end, we followed the fate and function of wild-type and LFA-1 deficient virus-specific CD8+ T cells and assessed the effect of blocking anti-LFA-1 monoclonal antibody in the outcome of infection. Our analysis of viral clearance and T cell responses using transcriptome profiling reveals a role for LFA-1 as a gatekeeper of effector T cell survival and dysfunction that when defective can predispose to LCMV infection.
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Affiliation(s)
- Mario Perro
- Harvard Medical School , Department of Microbiology and Immunobiology, Boston, Massachusetts, USA
| | - Matteo Iannacone
- Harvard Medical School , Department of Microbiology and Immunobiology, Boston, Massachusetts, USA
| | - Ulrich H von Andrian
- Harvard Medical School , Department of Microbiology and Immunobiology, Boston, Massachusetts, USA
| | - Antonio Peixoto
- Harvard Medical School , Department of Microbiology and Immunobiology, Boston, Massachusetts, USA
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20
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β2 Integrins differentially regulate γδ T cell subset thymic development and peripheral maintenance. Proc Natl Acad Sci U S A 2020; 117:22367-22377. [PMID: 32848068 DOI: 10.1073/pnas.1921930117] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The γδ T cells reside predominantly at barrier sites and play essential roles in immune protection against infection and cancer. Despite recent advances in the development of γδ T cell immunotherapy, our understanding of the basic biology of these cells, including how their numbers are regulated in vivo, remains poor. This is particularly true for tissue-resident γδ T cells. We have identified the β2 family of integrins as regulators of γδ T cells. β2-integrin-deficient mice displayed a striking increase in numbers of IL-17-producing Vγ6Vδ1+ γδ T cells in the lungs, uterus, and circulation. Thymic development of this population was normal. However, single-cell RNA sequencing revealed the enrichment of genes associated with T cell survival and proliferation specifically in β2-integrin-deficient IL-17+ cells compared to their wild-type counterparts. Indeed, β2-integrin-deficient Vγ6+ cells from the lungs showed reduced apoptosis ex vivo, suggesting that increased survival contributes to the accumulation of these cells in β2-integrin-deficient tissues. Furthermore, our data revealed an unexpected role for β2 integrins in promoting the thymic development of the IFNγ-producing CD27+ Vγ4+ γδ T cell subset. Together, our data reveal that β2 integrins are important regulators of γδ T cell homeostasis, inhibiting the survival of IL-17-producing Vγ6Vδ1+ cells and promoting the thymic development of the IFNγ-producing Vγ4+ subset. Our study introduces unprecedented mechanisms of control for γδ T cell subsets.
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21
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Abstract
Antibody-secreting plasma cells are the central pillars of humoral immunity. They are generated in a fundamental cellular restructuring process from naive B cells upon contact with antigen. This outstanding process is guided and controlled by a complex transcriptional network accompanied by a fascinating morphological metamorphosis, governed by the combined action of Blimp-1, Xbp-1 and IRF-4. The survival of plasma cells requires the intimate interaction with a specific microenvironment, consisting of stromal cells and cells of hematopoietic origin. Cell-cell contacts, cytokines and availability of metabolites such as glucose and amino acids modulate the survival abilities of plasma cells in their niches. Moreover, plasma cells have been shown to regulate immune responses by releasing cytokines. Furthermore, plasma cells are central players in autoimmune diseases and malignant transformation of plasma cells can result in the generation of multiple myeloma. Hence, the development of sophisticated strategies to deplete autoreactive plasma cells and myeloma cells represents a challenge for current and future research.
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Affiliation(s)
- Wolfgang Schuh
- Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger Center, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany.
| | - Dirk Mielenz
- Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger Center, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Hans-Martin Jäck
- Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger Center, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
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22
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Thierry GR, Gentek R, Bajenoff M. Remodeling of reactive lymph nodes: Dynamics of stromal cells and underlying chemokine signaling. Immunol Rev 2020; 289:42-61. [PMID: 30977194 DOI: 10.1111/imr.12750] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 01/28/2019] [Accepted: 01/31/2019] [Indexed: 12/19/2022]
Abstract
Lymph nodes (LNs) are secondary immune organs dispersed throughout the body. They are primarily composed of lymphocytes, "transient passengers" that are only present for a few hours. During this time, they extensively interact with a meshwork of stromal cells. Although these cells constitute less than 5% of all LN cells, they are integral to LN function: Stromal cells create a three-dimensional network that provides a rigid backbone for the transport of lymph and generates "roads" for lymphocyte migration. Beyond structural support, the LN stroma also produces survival signals for lymphocytes and provides nutrients, soluble factors, antigens, and immune cells collectively required for immune surveillance and the generation of adaptive immune responses. A unique feature of LNs is their ability to considerably and rapidly change size: the volume and cellularity of inflamed LNs can increase up to 20-fold before returning to homeostatic levels. This cycle will be repeated many times during life and is accommodated by stromal cells. The dynamics underlying this dramatic remodeling are subject of this review. We will first introduce the main types of LN stromal cells and explain their known functions. We will then discuss how these cells enable LN growth during immune responses, with a particular focus on underlying cellular mechanisms and molecular cues. Similarly, we will elaborate on stromal dynamics mediating the return to LN homeostasis, a process that is mechanistically much less understood than LN expansion.
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Affiliation(s)
- Guilhem R Thierry
- Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University, Marseille, France
| | - Rebecca Gentek
- Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University, Marseille, France
| | - Marc Bajenoff
- Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University, Marseille, France
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23
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Abstract
The variable outcome of Mycobacterium tuberculosis infection observed in natural populations is difficult to model in genetically homogeneous small-animal models. The newly developed Collaborative Cross (CC) represents a reproducible panel of genetically diverse mice that display a broad range of phenotypic responses to infection. We explored the genetic basis of this variation, focusing on a CC line that is highly susceptible to M. tuberculosis infection. This study identified multiple quantitative trait loci associated with bacterial control and cytokine production, including one that is caused by a novel loss-of-function mutation in the Itgal gene, which is necessary for T cell recruitment to the infected lung. These studies verify the multigenic control of mycobacterial disease in the CC panel, identify genetic loci controlling diverse aspects of pathogenesis, and highlight the utility of the CC resource. Host genetics plays an important role in determining the outcome of Mycobacterium tuberculosis
infection. We previously found that Collaborative Cross (CC) mouse strains differ in their susceptibility to M. tuberculosis and that the CC042/GeniUnc (CC042) strain suffered from a rapidly progressive disease and failed to produce the protective cytokine gamma interferon (IFN-γ) in the lung. Here, we used parallel genetic and immunological approaches to investigate the basis of CC042 mouse susceptibility. Using a population derived from a CC001/Unc (CC001) × CC042 intercross, we mapped four quantitative trait loci (QTL) underlying tuberculosis immunophenotypes (Tip1 to Tip4). These included QTL that were associated with bacterial burden, IFN-γ production following infection, and an IFN-γ-independent mechanism of bacterial control. Further immunological characterization revealed that CC042 animals recruited relatively few antigen-specific T cells to the lung and that these T cells failed to express the integrin alpha L (αL; i.e., CD11a), which contributes to T cell activation and migration. These defects could be explained by a CC042 private variant in the Itgal gene, which encodes CD11a and is found within the Tip2 interval. This 15-bp deletion leads to aberrant mRNA splicing and is predicted to result in a truncated protein product. The ItgalCC042 genotype was associated with all measured disease traits, indicating that this variant is a major determinant of susceptibility in CC042 mice. The combined effect of functionally distinct Tip variants likely explains the profound susceptibility of CC042 mice and highlights the multigenic nature of tuberculosis control in the Collaborative Cross.
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24
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Davenport B, Eberlein J, Nguyen TT, Victorino F, Jhun K, Abuirqeba H, van der Heide V, Heeger P, Homann D. Aging boosts antiviral CD8+T cell memory through improved engagement of diversified recall response determinants. PLoS Pathog 2019; 15:e1008144. [PMID: 31697793 PMCID: PMC6863560 DOI: 10.1371/journal.ppat.1008144] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 11/19/2019] [Accepted: 10/10/2019] [Indexed: 12/13/2022] Open
Abstract
The determinants of protective CD8+ memory T cell (CD8+TM) immunity remain incompletely defined and may in fact constitute an evolving agency as aging CD8+TM progressively acquire enhanced rather than impaired recall capacities. Here, we show that old as compared to young antiviral CD8+TM more effectively harness disparate molecular processes (cytokine signaling, trafficking, effector functions, and co-stimulation/inhibition) that in concert confer greater secondary reactivity. The relative reliance on these pathways is contingent on the nature of the secondary challenge (greater for chronic than acute viral infections) and over time, aging CD8+TM re-establish a dependence on the same accessory signals required for effective priming of naïve CD8+T cells in the first place. Thus, our findings reveal a temporal regulation of complementary recall response determinants that is consistent with the recently proposed "rebound model" according to which aging CD8+TM properties are gradually aligned with those of naïve CD8+T cells; our identification of a broadly diversified collection of immunomodulatory targets may further provide a foundation for the potential therapeutic "tuning" of CD8+TM immunity.
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Affiliation(s)
- Bennett Davenport
- Department of Anesthesiology & Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, United States of America
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado, United States of America
- Diabetes, Obesity & Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Jens Eberlein
- Department of Anesthesiology & Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, United States of America
| | - Tom T. Nguyen
- Department of Anesthesiology & Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, United States of America
| | - Francisco Victorino
- Department of Anesthesiology & Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, United States of America
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado, United States of America
| | - Kevin Jhun
- Diabetes, Obesity & Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Haedar Abuirqeba
- Diabetes, Obesity & Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Verena van der Heide
- Diabetes, Obesity & Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Peter Heeger
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Dirk Homann
- Department of Anesthesiology & Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, United States of America
- Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado, United States of America
- Diabetes, Obesity & Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
- * E-mail:
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25
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Lin C, Zhang Y, Zhang K, Zheng Y, Lu L, Chang H, Yang H, Yang Y, Wan Y, Wang S, Yuan M, Yan Z, Zhang R, He Y, Ge G, Wu D, Chen J. Fever Promotes T Lymphocyte Trafficking via a Thermal Sensory Pathway Involving Heat Shock Protein 90 and α4 Integrins. Immunity 2019; 50:137-151.e6. [PMID: 30650373 DOI: 10.1016/j.immuni.2018.11.013] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 06/27/2018] [Accepted: 11/08/2018] [Indexed: 01/03/2023]
Abstract
Fever is an evolutionarily conserved response that confers survival benefits during infection. However, the underlying mechanism remains obscure. Here, we report that fever promoted T lymphocyte trafficking through heat shock protein 90 (Hsp90)-induced α4 integrin activation and signaling in T cells. By inducing selective binding of Hsp90 to α4 integrins, but not β2 integrins, fever increased α4-integrin-mediated T cell adhesion and transmigration. Mechanistically, Hsp90 bound to the α4 tail and activated α4 integrins via inside-out signaling. Moreover, the N and C termini of one Hsp90 molecule simultaneously bound to two α4 tails, leading to dimerization and clustering of α4 integrins on the cell membrane and subsequent activation of the FAK-RhoA pathway. Abolishment of Hsp90-α4 interaction inhibited fever-induced T cell trafficking to draining lymph nodes and impaired the clearance of bacterial infection. Our findings identify the Hsp90-α4-integrin axis as a thermal sensory pathway that promotes T lymphocyte trafficking and enhances immune surveillance during infection.
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Affiliation(s)
- ChangDong Lin
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - YouHua Zhang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Kun Zhang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - YaJuan Zheng
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Ling Lu
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - HaiShuang Chang
- State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 201203, China
| | - Hui Yang
- State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 201203, China
| | - YanRong Yang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - YaoYing Wan
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - ShiHui Wang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - MengYa Yuan
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - ZhanJun Yan
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; Department of Orthopedics, First People's Hospital of Wujiang District, Suzhou City, Suzhou 215000, China
| | - RongGuang Zhang
- State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 201203, China
| | - YongNing He
- State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 201203, China
| | - GaoXiang Ge
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Dianqing Wu
- Vascular Biology and Therapeutic Program and Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520, USA
| | - JianFeng Chen
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
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26
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Dotan I, Allez M, Danese S, Keir M, Tole S, McBride J. The role of integrins in the pathogenesis of inflammatory bowel disease: Approved and investigational anti-integrin therapies. Med Res Rev 2019; 40:245-262. [PMID: 31215680 PMCID: PMC6973243 DOI: 10.1002/med.21601] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 04/12/2019] [Accepted: 05/13/2019] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease (IBD) is characterized by uncontrolled inflammation in the gastrointestinal tract. The underlying pathobiology of IBD includes an increase in infiltrating gut-homing lymphocytes. Although lymphocyte homing is typically a tightly regulated and stepwise process involving multiple integrins and adhesion molecules expressed on endothelial cells, the distinct roles of integrin-expressing immune cells is not fully understood in the pathology of IBD. In this review, we detail the involvement of integrins expressed on specific lymphocyte subsets in the pathogenesis of IBD and discuss the current status of approved and investigational integrin-targeted therapies.
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Affiliation(s)
- Iris Dotan
- Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Matthieu Allez
- Department of Gastroenterology, Hôpital Saint-Louis, AP-HP, INSERM U1160, University Denis Diderot, Paris, France
| | - Silvio Danese
- Gastrointestinal Immunopathology Laboratory and IBD Unit, Humanitas Clinical and Research Center, Milan, Italy
| | - Mary Keir
- Department of Research and Early Development, Genentech, South San Francisco, California
| | - Swati Tole
- Department of Product Development, Genentech, South San Francisco, California
| | - Jacqueline McBride
- Department of Research and Early Development, Genentech, South San Francisco, California
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27
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Sanchez JJ, Sanchez JE, Noor S, Ruffaner-Hanson CD, Davies S, Wagner CR, Jantzie LL, Mellios N, Savage DD, Milligan ED. Targeting the β2-integrin LFA-1, reduces adverse neuroimmune actions in neuropathic susceptibility caused by prenatal alcohol exposure. Acta Neuropathol Commun 2019; 7:54. [PMID: 30961664 PMCID: PMC6454692 DOI: 10.1186/s40478-019-0701-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 03/16/2019] [Indexed: 02/07/2023] Open
Abstract
Recently, moderate prenatal alcohol exposure (PAE) was shown to be a risk factor for peripheral neuropathy following minor nerve injury. This effect coincides with elevated spinal cord astrocyte activation and ex vivo immune cell reactivity assessed by proinflammatory cytokine interleukin (IL) -1β protein expression. Additionally, the β2-integrin adhesion molecule, lymphocyte function-associated antigen-1 (LFA-1), a factor that influences the expression of the proinflammatory/anti-inflammatory cytokine network is upregulated. Here, we examine whether PAE increases the proinflammatory immune environment at specific anatomical sites critical in the pain pathway of chronic sciatic neuropathy; the damaged sciatic nerve (SCN), the dorsal root ganglia (DRG), and the spinal cord. Additionally, we examine whether inhibiting LFA-1 or IL-1β actions in the spinal cord (intrathecal; i.t., route) could alleviate chronic neuropathic pain and reduce spinal and DRG glial activation markers, proinflammatory cytokines, and elevate anti-inflammatory cytokines. Results show that blocking the actions of spinal LFA-1 using BIRT-377 abolishes allodynia in PAE rats with sciatic neuropathy (CCI) of a 10 or 28-day duration. This effect is observed (utilizing immunohistochemistry; IHC, with microscopy analysis and protein quantification) in parallel with reduced spinal glial activation, IL-1β and TNFα expression. DRG from PAE rats with neuropathy reveal significant increases in satellite glial activation and IL-1β, while IL-10 immunoreactivity is reduced by half in PAE rats under basal and neuropathic conditions. Further, blocking spinal IL-1β with i.t. IL-1RA transiently abolishes allodynia in PAE rats, suggesting that IL-1β is in part, necessary for the susceptibility of adult-onset peripheral neuropathy caused by PAE. Chemokine mRNA analyses from SCN, DRG and spinal cord reveal that increased CCL2 occurs following CCI injury regardless of PAE and BIRT-377 treatment. These data demonstrate that PAE creates dysregulated proinflammatory IL-1β and TNFα /IL-10 responses to minor injury in the sciatic-DRG-spinal pain pathway. PAE creates a risk for developing peripheral neuropathies, and LFA-1 may be a novel therapeutic target for controlling dysregulated neuroimmune actions as a consequence of PAE.
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Affiliation(s)
- Joshua J. Sanchez
- Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, MSC08 4740, Albuquerque, NM 87131-0001 USA
| | - Jacob E. Sanchez
- Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, MSC08 4740, Albuquerque, NM 87131-0001 USA
| | - Shahani Noor
- Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, MSC08 4740, Albuquerque, NM 87131-0001 USA
| | - Chaselyn D. Ruffaner-Hanson
- Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, MSC08 4740, Albuquerque, NM 87131-0001 USA
| | - Suzy Davies
- Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, MSC08 4740, Albuquerque, NM 87131-0001 USA
| | - Carston R. Wagner
- Department of Medicinal Chemistry, University of Minnesota College of Pharmacy, Minneapolis, MN 55455 USA
| | - Lauren L. Jantzie
- Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, MSC08 4740, Albuquerque, NM 87131-0001 USA
- Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-0001 USA
| | - Nikolaos Mellios
- Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, MSC08 4740, Albuquerque, NM 87131-0001 USA
| | - Daniel D. Savage
- Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, MSC08 4740, Albuquerque, NM 87131-0001 USA
- Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-0001 USA
| | - Erin D. Milligan
- Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, MSC08 4740, Albuquerque, NM 87131-0001 USA
- Department of Anesthesiology and Critical Care Medicine, University of New Mexico Health Sciences Center, MSC08 4740, Albuquerque, NM 87131-0001 USA
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28
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Vojkovics D, Kellermayer Z, Gábris F, Schippers A, Wagner N, Berta G, Farkas K, Balogh P. Differential Effects of the Absence of Nkx2-3 and MAdCAM-1 on the Distribution of Intestinal Type 3 Innate Lymphoid Cells and Postnatal SILT Formation in Mice. Front Immunol 2019; 10:366. [PMID: 30891037 PMCID: PMC6413488 DOI: 10.3389/fimmu.2019.00366] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 02/13/2019] [Indexed: 01/08/2023] Open
Abstract
Seeding of leukocytes to developing lymphoid tissues in embryonic and early postnatal age and to the mucosa throughout adulthood depends on the interaction between endothelial MAdCAM-1 addressin and its cognate ligand α4β7 integrin. Nkx2-3 as a transcriptional regulator of MAdCAM-1 controls vascular patterning in visceral lymphoid tissues in mice, and has been identified as a susceptibility factor for inflammatory bowel diseases in humans, associated with lymphoid neogenesis in the inflamed intestines. The role of Nkx2-3 in the organogenesis of the solitary intestinal lymphoid tissues (SILTs) involving type 3 innate lymphoid cells (ILC3) is still unknown. Here we investigated the effect of Nkx2-3 on the postnatal distribution of intestinal ILC3s and the development of SILTs, comparing these to mice lacking MAdCAM-1, but preserving Nkx2-3. At 1 week of age small intestines (SI) contained significantly higher number of ILC3s relative to the colon, with a substantial reduction in MAdCAM-1−/− mice compared to C57BL/6 controls. One week later SI ILC3 number decreased in all genotypes, the number of colonic ILC3 of both Nkx2-3-deficient and Nkx2-3-heterozygous mice significantly increased. On the fourth postnatal week a further reduction of SI ILC3s was observed in both Nkx2-3-deficient and Nkx2-3-heterozygous mice, while in the colon the number of ILC3s showed a significant reduction in all genotypes. At 1 week of age only sporadic SILT components were present in all genotypes. By the second week mice deficient for either Nkx2-3 or MAdCAM-1 showed absence of SILT maturation compared to their relevant controls, lacking mature isolated lymphoid follicles (ILF). By the fourth week both Nkx2-3-deficient and Nkx2-3-heterozygous mice showed a similar distribution of ILFs relative to cryptopatches (CP), whereas in MAdCAM-1−/− mice CPs and immature ILFs were present, mature ILFs were scarce. Our data demonstrate that the complete absence of MAdCAM-1 partially impairs intestinal seeding of ILC3s and causes partial blockade of SILT maturation, without affecting peripheral lymph node development. In contrast, the inactivation of Nkx2-3 permits postnatal seeding, and its blocking effect on SILT maturation prevails at later stage, thus other adhesion molecules may compensate for the intestinal homing of ILC3s in the absence of MAdCAM-1.
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Affiliation(s)
- Dóra Vojkovics
- Department of Immunology and Biotechnology, Clinical Center, University of Pécs, Pécs, Hungary.,Lymphoid Organogenesis Research Group, Szentágothai Research Center, University of Pécs, Pécs, Hungary
| | - Zoltán Kellermayer
- Department of Immunology and Biotechnology, Clinical Center, University of Pécs, Pécs, Hungary.,Lymphoid Organogenesis Research Group, Szentágothai Research Center, University of Pécs, Pécs, Hungary
| | - Fanni Gábris
- Department of Immunology and Biotechnology, Clinical Center, University of Pécs, Pécs, Hungary.,Lymphoid Organogenesis Research Group, Szentágothai Research Center, University of Pécs, Pécs, Hungary
| | - Angela Schippers
- Department of Pediatrics, University Hospital RWTH, Aachen, Germany
| | - Norbert Wagner
- Department of Pediatrics, University Hospital RWTH, Aachen, Germany
| | - Gergely Berta
- Central Electron Microscope Laboratory, Department of Medical Biology, Medical School, University of Pécs, Pécs, Hungary
| | - Kornélia Farkas
- Department of Bioanalytics, Medical School, University of Pécs, Pécs, Hungary
| | - Péter Balogh
- Department of Immunology and Biotechnology, Clinical Center, University of Pécs, Pécs, Hungary.,Lymphoid Organogenesis Research Group, Szentágothai Research Center, University of Pécs, Pécs, Hungary
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29
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Molecular basis for autoinhibition of RIAM regulated by FAK in integrin activation. Proc Natl Acad Sci U S A 2019; 116:3524-3529. [PMID: 30733287 DOI: 10.1073/pnas.1818880116] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
RAP1-interacting adapter molecule (RIAM) mediates RAP1-induced integrin activation. The RAS-association (RA) segment of the RA-PH module of RIAM interacts with GTP-bound RAP1 and phosphoinositol 4,5 bisphosphate but this interaction is inhibited by the N-terminal segment of RIAM. Here we report the structural basis for the autoinhibition of RIAM by an intramolecular interaction between the IN region (aa 27-93) and the RA-PH module. We solved the crystal structure of IN-RA-PH to a resolution of 2.4-Å. The structure reveals that the IN segment associates with the RA segment and thereby suppresses RIAM:RAP1 association. This autoinhibitory configuration of RIAM can be released by phosphorylation at Tyr45 in the IN segment. Specific inhibitors of focal adhesion kinase (FAK) blocked phosphorylation of Tyr45, inhibited stimulated translocation of RIAM to the plasma membrane, and inhibited integrin-mediated cell adhesion in a Tyr45-dependent fashion. Our results reveal an unusual regulatory mechanism in small GTPase signaling by which the effector molecule is autoinhibited for GTPase interaction, and a modality of integrin activation at the level of RIAM through a FAK-mediated feedforward mechanism that involves reversal of autoinhibition by a tyrosine kinase associated with integrin signaling.
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30
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Assing K, Nielsen C, Hansen HT, Jakobsen MA, Skogstrand K, Brasch-Andersen C, Hartling UB, Fisker N. CD18 is redundant for the response to multiple vaccines: A case study. Pediatr Allergy Immunol 2019; 30:136-139. [PMID: 30312521 DOI: 10.1111/pai.12989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- Kristian Assing
- Department of Clinical Immunology, Odense University Hospital, Odense, Denmark
| | - Christian Nielsen
- Department of Clinical Immunology, Odense University Hospital, Odense, Denmark
| | - Henrik T Hansen
- Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark
| | - Marianne A Jakobsen
- Department of Clinical Immunology, Odense University Hospital, Odense, Denmark
| | - Kristin Skogstrand
- Department of Congenital Disorders, Center for Neonatal Screening, Statens Serum Institut, Copenhagen, Denmark
| | | | - Ulla B Hartling
- Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark
| | - Niels Fisker
- Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark
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31
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Abstract
Regulated migration of T-lymphocytes through high endothelial venules and secondary lymphoid organs is necessary for an adaptive immune response. Uncontrolled trafficking of T-cells is implicated in many pathological conditions, including autoimmune disorders, such as psoriasis and inflammatory bowel disease. T-cell migration is regulated mainly by the αLβ2 integrin receptor LFA-1, which interacts primarily with its cognate ligand ICAM-1 expressed on the endothelium. This interaction triggers a plethora of downstream signaling pathways, which are not fully understood. Thus, in order to dissect the signal transduction processes at molecular levels and phenotypic changes in migrating T-cells, a laboratory model mimicking T-cell motility is important. Here, we describe a simple and highly reproducible in vitro model to study T-cell migration.
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32
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Vicente-Manzanares M, Sánchez-Madrid F. Targeting the integrin interactome in human disease. Curr Opin Cell Biol 2018; 55:17-23. [DOI: 10.1016/j.ceb.2018.05.010] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 05/07/2018] [Accepted: 05/14/2018] [Indexed: 12/21/2022]
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33
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T cell microvilli constitute immunological synaptosomes that carry messages to antigen-presenting cells. Nat Commun 2018; 9:3630. [PMID: 30194420 PMCID: PMC6128830 DOI: 10.1038/s41467-018-06090-8] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 08/17/2018] [Indexed: 12/22/2022] Open
Abstract
Microvilli on T cells have been proposed to survey surfaces of antigen-presenting cells (APC) or facilitate adhesion under flow; however, whether they serve essential functions during T cell activation remains unclear. Here we show that antigen-specific T cells deposit membrane particles derived from microvilli onto the surface of cognate antigen-bearing APCs. Microvilli carry T cell receptors (TCR) at all stages of T cell activation and are released as large TCR-enriched, T cell microvilli particles (TMP) in a process of trogocytosis. These microvilli exclusively contain protein arrestin-domain-containing protein 1, which is directly involved in membrane budding and, in combination with vacuolar protein-sorting-associated protein 4, transforms large TMPs into smaller, exosome-sized TMPs. Notably, TMPs from CD4+ T cells are enriched with LFA-2/CD2 and various cytokines involved in activating dendritic cells. Collectively, these results demonstrate that T cell microvilli constitute “immunological synaptosomes” that carry T cell messages to APCs. Microvilli can participate in adhesion or migration of T cells, but whether they are involved in function regulation is unclear. Here the authors show that T cell microvilli form budding vesicles containing T cell signalling components for deposition onto antigen presenting cells (APC) and modulation of APC functions.
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34
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Wang S, Wu C, Zhang Y, Zhong Q, Sun H, Cao W, Ge G, Li G, Zhang XF, Chen J. Integrin α4β7 switches its ligand specificity via distinct conformer-specific activation. J Cell Biol 2018; 217:2799-2812. [PMID: 29789438 PMCID: PMC6080939 DOI: 10.1083/jcb.201710022] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Revised: 02/11/2018] [Accepted: 05/03/2018] [Indexed: 12/16/2022] Open
Abstract
CCL25, CXCL10, and Mn2+ induce three distinct active conformations of integrin α4β7, which have selective high affinity for either MAdCAM-1, VCAM-1, or nonselective high affinity for both ligands. Via this mechanism, integrin α4β7 adopts different active conformations to switch its ligand-binding specificity. Chemokine (C-C motif) ligand 25 (CCL25) and C-X-C motif chemokine 10 (CXCL10) induce the ligand-specific activation of integrin α4β7 to mediate the selective adhesion of lymphocytes to mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1) or vascular cell adhesion molecule-1 (VCAM-1). However, the mechanism underlying the selective binding of different ligands by α4β7 remains obscure. In this study, we demonstrate that CCL25 and CXCL10 induce distinct active conformers of α4β7 with a high affinity for either MAdCAM-1 or VCAM-1. Single-cell force measurements show that CCL25 increases the affinity of α4β7 for MAdCAM-1 but decreases its affinity for VCAM-1, whereas CXCL10 has the opposite effect. Structurally, CCL25 induces a more extended active conformation of α4β7 compared with CXCL10-activated integrin. These two distinct intermediate open α4β7 conformers selectively bind to MAdCAM-1 or VCAM-1 by distinguishing their immunoglobulin domain 2. Notably, Mn2+ fully opens α4β7 with a high affinity for both ligands. Thus, integrin α4β7 adopts different active conformations to switch its ligand-binding specificity.
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Affiliation(s)
- ShiHui Wang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - ChenYu Wu
- Department of Bioengineering and Department of Mechanical Engineering and Mechanics, Lehigh University, Bethlehem, PA
| | - YueBin Zhang
- Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, China
| | - QingLu Zhong
- Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, China
| | - Hao Sun
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - WenPeng Cao
- Department of Bioengineering and Department of Mechanical Engineering and Mechanics, Lehigh University, Bethlehem, PA
| | - GaoXiang Ge
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - GuoHui Li
- Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, China
| | - X Frank Zhang
- Department of Bioengineering and Department of Mechanical Engineering and Mechanics, Lehigh University, Bethlehem, PA
| | - JianFeng Chen
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
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35
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Zhang Q, Waqas Y, Yang P, Sun X, Liu Y, Ahmed N, Chen B, Li Q, Hu L, Huang Y, Chen H, Hu B, Chen Q. Cytological study on the regulation of lymphocyte homing in the chicken spleen during LPS stimulation. Oncotarget 2018; 8:7405-7419. [PMID: 28061467 PMCID: PMC5352331 DOI: 10.18632/oncotarget.14502] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2016] [Accepted: 12/27/2016] [Indexed: 12/11/2022] Open
Abstract
The immune function of the chicken spleen depends on its different compartments of red and white pulps, but little is known about the mechanism underlying lymphocyte homing towards the different compartments. In the present study, the role of lymphocyte homing in the chicken spleen was investigated during lipopolysaccharide (LPS) stimulation. Morphological analysis demonstrated the cuboidal endothelial cells of the splenic sheathed capillary facilitated the passage of lymphocyte homing to the chicken spleen. The tissue-specific adhesion molecules- vascular cell adhesion molecule-1 (VCAM-1) and mucosal addressin cell adhesion molecule-1 (MADCAM-1) expressed on the sheathed capillary, which suggested the high endothelial venule (HEV)-like vessels of the chicken spleen. Electron microscope analysis showed LPS activated the endothelium of the sheathed capillary and recruited lymphocytes to the chicken spleen. Transferring of 5, 6- carboxyfluorescein diacetate, succinimidyl ester (CFSE) labeled lymphocytes depicted the rout of lymphocyte homing to the compartments of the chicken spleen was from the white pulp to the red pulp. Furthermore, the mRNA and protein levels of adhesion molecular integrin β1 and VCAM-1 increased after LPS stimulation. The mechanism underlying the integrin β1 and VCAM-1 during LPS stimulation might be associated with the integrin linked kinase (ILK)- dependent regulation of protein kinase B (PKB/AKT). This study firstly shows lymphocyte homing in the chicken spleen after LPS-induced inflammation. These results contribute to our knowledge of comparative immunology and provide a better means for investigating the pharmacological strategies concerning the possible role of lymphocyte homing in inflammation and immunological reactions in infectious disease.
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Affiliation(s)
- Qian Zhang
- Laboratory of Animal Cell Biology and Embryology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China.,Key Laboratory of Antibody Techniques of Ministry of Health, Nanjing Medical University, Nanjing, China
| | - Yasir Waqas
- Laboratory of Animal Cell Biology and Embryology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Ping Yang
- Laboratory of Animal Cell Biology and Embryology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Xuejing Sun
- Laboratory of Animal Cell Biology and Embryology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Yi Liu
- Laboratory of Animal Cell Biology and Embryology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Nisar Ahmed
- Laboratory of Animal Cell Biology and Embryology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Bing Chen
- Laboratory of Animal Cell Biology and Embryology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Quanfu Li
- Laboratory of Animal Cell Biology and Embryology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Lisi Hu
- Laboratory of Animal Cell Biology and Embryology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Yufei Huang
- Laboratory of Animal Cell Biology and Embryology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Hong Chen
- Laboratory of Animal Cell Biology and Embryology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Bing Hu
- Biological experiment and Teaching Center, College of Life Sciences, Nanjing Agricultural University, Nanjing, China
| | - Qiusheng Chen
- Laboratory of Animal Cell Biology and Embryology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
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Capece T, Walling BL, Lim K, Kim KD, Bae S, Chung HL, Topham DJ, Kim M. A novel intracellular pool of LFA-1 is critical for asymmetric CD8 + T cell activation and differentiation. J Cell Biol 2017; 216:3817-3829. [PMID: 28954823 PMCID: PMC5674876 DOI: 10.1083/jcb.201609072] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 01/13/2017] [Accepted: 07/11/2017] [Indexed: 11/22/2022] Open
Abstract
The integrin lymphocyte function-associated antigen 1 (LFA-1; CD11a/CD18) is a key T cell adhesion receptor that mediates stable interactions with antigen-presenting cell (APC), as well as chemokine-mediated migration. Using our newly generated CD11a-mYFP knock-in mice, we discovered that naive CD8+ T cells reserve a significant intracellular pool of LFA-1 in the uropod during migration. Intracellular LFA-1 quickly translocated to the cell surface with antigenic stimulus. Importantly, the redistribution of intracellular LFA-1 at the contact with APC was maintained during cell division and led to an unequal inheritance of LFA-1 in divided T cells. The daughter CD8+ T cells with disparate LFA-1 expression showed different patterns of migration on ICAM-1, APC interactions, and tissue retention, as well as altered effector functions. In addition, we identified Rab27 as an important regulator of the intracellular LFA-1 translocation. Collectively, our data demonstrate that an intracellular pool of LFA-1 in naive CD8+ T cells plays a key role in T cell activation and differentiation.
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Affiliation(s)
- Tara Capece
- Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY
| | - Brandon L Walling
- Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY
| | - Kihong Lim
- Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY
| | - Kyun-Do Kim
- Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY
| | - Seyeon Bae
- Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY
| | - Hung-Li Chung
- Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY
| | - David J Topham
- Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY
| | - Minsoo Kim
- Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY
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Gurevich I, Feferman T, Milo I, Tal O, Golani O, Drexler I, Shakhar G. Active dissemination of cellular antigens by DCs facilitates CD8 + T-cell priming in lymph nodes. Eur J Immunol 2017; 47:1802-1818. [PMID: 28872666 DOI: 10.1002/eji.201747042] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 07/03/2017] [Accepted: 08/29/2017] [Indexed: 11/11/2022]
Abstract
Antigen (Ag) specific activation of naïve T cells by migrating dendritic cells (DCs) is a highly efficient process, although the chances for their colocalization in lymph nodes (LNs) appear low. Ag presentation may be delegated from Ag-donor DCs to the abundant resident DCs, but the routes of Ag transfer and how it facilitates T-cell activation remain unclear. We visualized CD8+ T cell-DC interactions to study the sites, routes, and cells mediating Ag transfer in mice. In vitro, Ag transfer from isolated ovalbumin (OVA)+ bone marrow (BM) DCs triggered widespread arrest, Ca2+ flux, and CD69 upregulation in OT-I T cells contacting recipient DCs. Intravital two-photon imaging revealed that survival of Ag-donor DCs in LNs was required for Ag dissemination among resident CD11c+ DCs. Upon interaction with recipient DCs, CD8+ T cells clustered, upregulated CD69, proliferated and differentiated into effectors. Few DCs sufficed for activation, and for efficient Ag dissemination lymphocyte function associated antigen 1 (LFA-1) expression on recipient DCs was essential. Similar findings characterized DCs infected with a replication-deficient OVA-expressing Vaccinia virus known to downregulate MHC-I. Overall, active Ag dissemination from live incoming DCs helped activate CD8+ T cells by increasing the number of effective presenting cells and salvaged T-cell priming when Ag-donor DCs could not present Ag.
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Affiliation(s)
- Irina Gurevich
- Department of Immunology and Veterinary Services, Weizmann Institute of Science, Rehovot, Israel.,Dermatology Department, School of Medicine, Stanford, California
| | - Tali Feferman
- Department of Immunology and Veterinary Services, Weizmann Institute of Science, Rehovot, Israel
| | - Idan Milo
- Department of Immunology and Veterinary Services, Weizmann Institute of Science, Rehovot, Israel.,Immunology Department, Pasteur Institute, Paris, France
| | - Orna Tal
- Department of Immunology and Veterinary Services, Weizmann Institute of Science, Rehovot, Israel
| | - Ofra Golani
- Department of Veterinary Services, Weizmann Institute of Science, Rehovot, Israel
| | - Ingo Drexler
- Institute for Virology, Heinrich-Heine-University, Düsseldorf, Germany
| | - Guy Shakhar
- Department of Immunology and Veterinary Services, Weizmann Institute of Science, Rehovot, Israel
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Harnessing Advances in T Regulatory Cell Biology for Cellular Therapy in Transplantation. Transplantation 2017; 101:2277-2287. [PMID: 28376037 DOI: 10.1097/tp.0000000000001757] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cellular therapy with CD4FOXP3 T regulatory (Treg) cells is a promising strategy to induce tolerance after solid-organ transplantation or prevent graft-versus-host disease after transfer of hematopoietic stem cells. Treg cells currently used in clinical trials are either polyclonal, donor- or antigen-specific. Aside from variations in isolation and expansion protocols, however, most therapeutic Treg cell-based products are much alike. Ongoing basic science work has provided considerable new insight into multiple facets of Treg cell biology, including their stability, homing, and functional specialization; integrating these basic science discoveries with clinical efforts will support the development of next-generation therapeutic Treg cells with enhanced efficacy. In this review, we summarize recent advances in knowledge of how Treg cells home to lymphoid and peripheral tissues, and control antibody production and tissue repair. We also discuss newly appreciated pathways that modulate context-specific Treg cell function and stability. Strategies to improve and tailor Treg cells for cell therapy to induce transplantation tolerance are highlighted.
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39
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Zaretsky I, Atrakchi O, Mazor RD, Stoler-Barak L, Biram A, Feigelson SW, Gitlin AD, Engelhardt B, Shulman Z. ICAMs support B cell interactions with T follicular helper cells and promote clonal selection. J Exp Med 2017; 214:3435-3448. [PMID: 28939548 PMCID: PMC5679169 DOI: 10.1084/jem.20171129] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 08/07/2017] [Accepted: 08/28/2017] [Indexed: 01/13/2023] Open
Abstract
The molecular mechanism governing affinity-based B cell selection for germinal center colonization is unclear. Zaretsky et al. show that B cell ICAMs promote efficient B cell selection for clonal expansion by supporting sustained interactions with T follicular helper cells. The germinal center (GC) reaction begins with a diverse and expanded group of B cell clones bearing a wide range of antibody affinities. During GC colonization, B cells engage in long-lasting interactions with T follicular helper (Tfh) cells, a process that depends on antigen uptake and antigen presentation to the Tfh cells. How long-lasting T–B interactions and B cell clonal expansion are regulated by antigen presentation remains unclear. Here, we use in vivo B cell competition models and intravital imaging to examine the adhesive mechanisms governing B cell selection for GC colonization. We find that intercellular adhesion molecule 1 (ICAM-1) and ICAM-2 on B cells are essential for long-lasting cognate Tfh–B cell interactions and efficient selection of low-affinity B cell clones for proliferative clonal expansion. Thus, B cell ICAMs promote efficient antibody immune response by enhancement of T cell help to cognate B cells.
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Affiliation(s)
- Irina Zaretsky
- Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel
| | - Ofir Atrakchi
- Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel
| | - Roei D Mazor
- Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel
| | - Liat Stoler-Barak
- Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel
| | - Adi Biram
- Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel
| | - Sara W Feigelson
- Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel
| | - Alexander D Gitlin
- Laboratory of Molecular Immunology, The Rockefeller University, New York, NY
| | | | - Ziv Shulman
- Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel
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Borger JG, Morrison VL, Filby A, Garcia C, Uotila LM, Simbari F, Fagerholm SC, Zamoyska R. Caveolin-1 Influences LFA-1 Redistribution upon TCR Stimulation in CD8 T Cells. THE JOURNAL OF IMMUNOLOGY 2017. [PMID: 28637901 PMCID: PMC5523581 DOI: 10.4049/jimmunol.1700431] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
TCR stimulation by peptide-MHC complexes on APCs requires precise reorganization of molecules into the area of cellular contact to form an immunological synapse from where T cell signaling is initiated. Caveolin (Cav)1, a widely expressed transmembrane protein, is involved in the regulation of membrane composition, cellular polarity and trafficking, and the organization of signal transduction pathways. The presence of Cav1 protein in T cells was identified only recently, and its function in this context is not well understood. We show that Cav1-knockout CD8 T cells have a reduction in membrane cholesterol and sphingomyelin, and upon TCR triggering they exhibit altered morphology and polarity, with reduced effector function compared with Cav1 wild-type CD8 T cells. In particular, redistribution of the β2 integrin LFA-1 to the immunological synapse is compromised in Cav1-knockout T cells, as is the ability of LFA-1 to form high-avidity interactions with ICAM-1. Our results identify a role for Cav1 in membrane organization and β2 integrin function in primary CD8 T cells.
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Affiliation(s)
- Jessica G Borger
- Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom
| | | | - Andrew Filby
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom; and
| | - Celine Garcia
- Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom
| | - Liisa M Uotila
- Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland
| | - Fabio Simbari
- Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom
| | | | - Rose Zamoyska
- Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom;
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Jörger AK, Liu L, Fehlner K, Weisser T, Cheng Z, Lu M, Höchst B, Bolzer A, Wang B, Hartmann D, Assfalg V, Sunami Y, Schlitter AM, Friess H, Hüser N, Laschinger M. Impact of NKT Cells and LFA-1 on Liver Regeneration under Subseptic Conditions. PLoS One 2016; 11:e0168001. [PMID: 27977747 PMCID: PMC5158001 DOI: 10.1371/journal.pone.0168001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 11/23/2016] [Indexed: 01/13/2023] Open
Abstract
Background Activation of the immune system in terms of subseptic conditions during liver regeneration is of paramount clinical importance. However, little is known about molecular mechanisms and their mediators that control hepatocyte proliferation. We sought to determine the functional role of immune cells, especially NKT cells, in response to partial hepatectomy (PH), and to uncover the impact of the integrin lymphocyte function-associated antigen-1 (LFA-1) on liver regeneration in a subseptic setting. Methods Wild-type (WT) and LFA-1-/- mice underwent a 2/3 PH and low-dose lipopolysaccharid (LPS) application. Hepatocyte proliferation, immune cell infiltration, and cytokine profile in the liver parenchyma were determined. Results Low-dose LPS application after PH results in a significant delay of liver regeneration between 48h and 72h, which is associated with a reduced number of CD3+ cells within the regenerating liver. In absence of LFA-1, an impaired regenerative capacity was observed under low-dose LPS application. Analysis of different leukocyte subpopulations showed less CD3+NK1.1+ NKT cells in the liver parenchyma of LFA-1-/- mice after PH and LPS application compared to WT controls, while CD3-NK1.1+ NK cells markedly increased. Concordantly with this observation, lower levels of NKT cell related cytokines IL-12 and IL-23 were expressed in the regenerating liver of LFA-1-/- mice, while the expression of NK cell-associated CCL5 and IL-10 was increased compared to WT mice. Conclusion A subseptic situation negatively alters hepatocyte proliferation. Within this scenario, we suggest an important impact of NKT cells and postulate a critical function for LFA-1 during processes of liver regeneration.
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Affiliation(s)
- Ann-Kathrin Jörger
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Lei Liu
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Karin Fehlner
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Tanja Weisser
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Zhangjun Cheng
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Miao Lu
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Bastian Höchst
- Institute of Molecular Immunology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | | | - Baocai Wang
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Daniel Hartmann
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Volker Assfalg
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Yoshiaki Sunami
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | | | - Helmut Friess
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Norbert Hüser
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
- * E-mail:
| | - Melanie Laschinger
- Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
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Teoh CM, Tan SSL, Tran T. Integrins as Therapeutic Targets for Respiratory Diseases. Curr Mol Med 2016; 15:714-34. [PMID: 26391549 PMCID: PMC5427774 DOI: 10.2174/1566524015666150921105339] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Revised: 09/09/2015] [Accepted: 09/19/2015] [Indexed: 01/14/2023]
Abstract
Integrins are a large family of transmembrane heterodimeric proteins that constitute the main receptors for extracellular matrix components. Integrins were initially thought to be primarily involved in the maintenance of cell adhesion and tissue integrity. However, it is now appreciated that integrins play important roles in many other biological processes such as cell survival, proliferation, differentiation, migration, cell shape and polarity. Lung cells express numerous combinations and permutations of integrin heterodimers. The complexity and diversity of different integrin heterodimers being implicated in different lung diseases present a major challenge for drug development. Here we provide a comprehensive overview of the current knowledge of integrins from studies in cell culture to integrin knockout mouse models and provide an update of results from clinical trials for which integrins are therapeutic targets with a focus on respiratory diseases (asthma, emphysema, pneumonia, lung cancer, pulmonary fibrosis and sarcoidosis).
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Affiliation(s)
| | | | - T Tran
- Department of Physiology, MD9, 2 Medical Drive, National University of Singapore, Singapore 117597, Singapore.
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Wolkerstorfer S, Schwaiger E, Rinnerthaler M, Karina Gratz I, Zoegg T, Brandstetter H, Achatz-Straussberger G. HAX1 deletion impairs BCR internalization and leads to delayed BCR-mediated apoptosis. Cell Mol Immunol 2016; 13:451-61. [PMID: 25864916 PMCID: PMC4947813 DOI: 10.1038/cmi.2015.18] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Accepted: 02/11/2015] [Indexed: 12/25/2022] Open
Abstract
Deletion of HAX1 in mice causes a severe reduction in the numbers of lymphocytes in the bone marrow and in the spleen. Additionally, B220(+) B progenitor cells in the bone marrow are reduced, suggesting an important function of HAX1 in B cell development. HAX1 is thought to play a protective role in apoptotic processes; therefore, we investigated the role of HAX1 in bone marrow B progenitor cells and splenic B cells. We did not observe an effect on the survival of Hax1(-/-) bone marrow cells but detected enhanced survival of splenic Hax1(-/-) B cells upon in vitro starvation/growth-factor withdrawal. To explain this apparent inconsistency with previous reports of HAX1 function, we also studied the B cell receptor (BCR)-induced apoptosis of IgM-stimulated splenic naïve B cells and found that apoptosis decreased in these cells. We further found impaired internalization of the BCR from Hax1(-/-) splenic B cells after IgM crosslinking; this impaired internalization may result in decreased BCR signaling and, consequently, decreased BCR-mediated apoptosis. We measured HAX1 binding to the cytoplasmic domains of different Ig subtypes and identified KVKWI(V)F as the putative binding motif for HAX1 within the cytoplasmic domains. Because this motif can be found in almost all Ig subtypes, it is likely that HAX1 plays a general role in BCR-mediated internalization events and BCR-mediated apoptosis.
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Affiliation(s)
| | | | - Mark Rinnerthaler
- Department of Cell Biology, University of Salzburg, Salzburg, Austria
| | - Iris Karina Gratz
- Department of Molecular Biology, University of Salzburg, Salzburg, Austria
- Department of Dermatology, University of California San Francisco, CA, USA
- Department of Dermatology, Division of Molecular Dermatology and EB House Austria, Paracelsus Medical University, Salzburg, Austria
| | - Thomas Zoegg
- Department of Molecular Biology, University of Salzburg, Salzburg, Austria
| | - Hans Brandstetter
- Department of Molecular Biology, University of Salzburg, Salzburg, Austria
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Kamel AM, El-Sharkawy NM, Osman RA, Abd El-Fattah EK, El-Noshokaty E, Abd El-Hamid T, Kandeel EZ. Adhesion molecules expression in CLL: Potential impact on clinical and hematological parameters. J Egypt Natl Canc Inst 2016; 28:31-7. [PMID: 26873628 DOI: 10.1016/j.jnci.2016.01.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Revised: 01/09/2016] [Accepted: 01/12/2016] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND B-cell chronic lymphocytic leukemia (CLL) is marked by the accumulation of CD5+ B lymphocytes within the blood, bone marrow (BM), and secondary lymphoid tissues. Abnormalities in the expression and function of cell adhesion molecules may account for the patterns of intra-nodal growth and hematogenous spread of the malignant cells. Chemokines and integrin-mediated adhesion and trans-endothelial migration (TEM) are central aspects in trafficking and retention of hematopoietic cells in the BM and lymphoid organs. AIM OF THE WORK This work was conducted to study adhesion molecules status in CLL and its potential impact on both hematological and clinical parameters. PATIENTS AND METHODS The study included 78 newly diagnosed CLL patients. Immunophenotyping was performed on peripheral blood using the chronic lymphoid panel. Adhesion molecules (CD11a, CD11b, CD49d, CD49C, CD29 and CD38) were tested using monoclonal antibodies and analyzed by Flow Cytometry. RESULTS Positive correlation was encountered between adhesion molecules: CD38 with CD49d (r=0.25, p=0.028), CD11a with CD11b, CD49d and CD29 (r=0.394, p=0.001; r=0.441, p=<0.01 and r=0.446, p<0.01 respectively) and CD29 with CD49c and CD49d (r=0.437, p<0.01; r=0.674, p<0.01 respectively). CD49c showed negative correlation with Rai staging (r=-0.269, p=0.033). CD11a and CD29 showed a significant relation with splenomegaly (p=0.04 and 0.03 respectively) and CD49d showed a significant relation with lymphadenopathy (p=0.02). CONCLUSION The level of different adhesion molecules expression in CLL is apparently reflected on the potential migratory behavior of the leukemic cells to different organs.
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Affiliation(s)
- Azza M Kamel
- Clinical Pathology Department, NCI, Cairo University, Fom El-Khalig Square, Kasr El-Aini St., Cairo 11796, Egypt.
| | - Nahla M El-Sharkawy
- Clinical Pathology Department, NCI, Cairo University, Fom El-Khalig Square, Kasr El-Aini St., Cairo 11796, Egypt.
| | - Randa A Osman
- Clinical Pathology Department, NCI, Cairo University, Fom El-Khalig Square, Kasr El-Aini St., Cairo 11796, Egypt.
| | - Eman K Abd El-Fattah
- Clinical Pathology Department, NCI, Cairo University, Fom El-Khalig Square, Kasr El-Aini St., Cairo 11796, Egypt.
| | - Essam El-Noshokaty
- Clinical Pathology Department, NCI, Cairo University, Fom El-Khalig Square, Kasr El-Aini St., Cairo 11796, Egypt.
| | - Thoraya Abd El-Hamid
- Medical Oncology Department, NCI, Cairo University, Fom El-Khalig Square, Kasr El-Aini St., Cairo 11796, Egypt.
| | - Eman Z Kandeel
- Clinical Pathology Department, NCI, Cairo University, Fom El-Khalig Square, Kasr El-Aini St., Cairo 11796, Egypt.
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Liu JR, Han X, Soriano SG, Yuki K. Leukocyte function-associated antigen-1 deficiency impairs responses to polymicrobial sepsis. World J Clin Cases 2015; 3:793-806. [PMID: 26380827 PMCID: PMC4568529 DOI: 10.12998/wjcc.v3.i9.793] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2015] [Revised: 04/10/2015] [Accepted: 06/15/2015] [Indexed: 02/05/2023] Open
Abstract
AIM To determine the role of leukocyte function-associated antigen-1 (LFA-1) in polymicrobial sepsis model in mice. METHODS Cecal ligation and puncture model was used to study polymicrobial sepsis in wild type and LFA-1 knockout (KO) (= CD11a KO) mice. Their survivals were examined. Neutrophil recruitment to the abdominal cavity, bacterial tissue load and bacterial killing by neutrophils, tissue cytokine profiles, and serum cytokines were examined. Apoptosis of tissues was assessed using cleaved-caspase 3 and TUNNEL staining. The recruitment of neutrophils to various tissues was assessed using myeloperoxidase staining or measuring myeloperoxidase activity. RESULTS LFA-1 deficiency significantly decreased survival (P = 0.0024) with the reduction of neutrophil recruitment to the abdominal cavity and higher bacterial load in blood. It was also associated with increased apoptosis in spleen and more organ injuries probed by interleukin-6 mRNA level. However, the deficiency of LFA-1 did not prevent neutrophil recruitment to lung, liver, spleen or kidney, which suggested the existence of LFA-1 independent recruitment mechanism in these organs. CONCLUSION LFA-1 deficiency did not attenuate neutrophil recruitment to various organs to adequately mitigate secondary tissue injury in sepsis. It was associated with decreased neutrophil recruitment to the abdominal cavity, higher bacterial load, leading to increased mortality in an abdominal, polymicrobial sepsis.
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Loss of the Rap1 effector RIAM results in leukocyte adhesion deficiency due to impaired β2 integrin function in mice. Blood 2015; 126:2704-12. [PMID: 26337492 DOI: 10.1182/blood-2015-05-647453] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2015] [Accepted: 08/24/2015] [Indexed: 01/13/2023] Open
Abstract
Talin is an integrin adaptor, which controls integrin activity in all hematopoietic cells. How intracellular signals promote talin binding to the integrin tail leading to integrin activation is still poorly understood, especially in leukocytes. In vitro studies identified an integrin activation complex whose formation is initiated by the interaction of active, guanosine triphosphate (GTP)-bound Ras-related protein 1 (Rap1) with the adapter protein Rap1-GTP-interacting adapter molecule (RIAM) followed by the recruitment of talin to the plasma membrane. Unexpectedly, loss-of-function studies in mice have shown that the talin-activating role of RIAM is neither required for development nor for integrin activation in platelets. In this study, we show that leukocyte integrin activation critically depends on RIAM both in vitro and in vivo. RIAM deficiency results in a loss of β2 integrin activation in multiple leukocyte populations, impaired leukocyte adhesion to inflamed vessels, and accumulation in the circulation. Surprisingly, however, the major leukocyte β1 integrin family member, α4β1, was only partially affected by RIAM deficiency in leukocytes. Thus, although talin is an essential, shared regulator of all integrin classes expressed by leukocytes, we report that β2 and α4 integrins use different RIAM-dependent and -independent pathways to undergo activation by talin.
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47
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Rap1 and its effector RIAM are required for lymphocyte trafficking. Blood 2015; 126:2695-703. [PMID: 26324702 DOI: 10.1182/blood-2015-05-644104] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 08/24/2015] [Indexed: 12/28/2022] Open
Abstract
Regulation of integrins is critical for lymphocyte adhesion to endothelium and trafficking through secondary lymphoid organs. Inside-out signaling to integrins is mediated by the small GTPase Rap1. Two effectors of Rap1 regulate integrins, RapL and Rap1 interacting adaptor molecule (RIAM). Using mice conditionally deficient in both Rap1a and Rap1b and mice null for RIAM, we show that the Rap1/RIAM module is not required for T- or B-cell development but is essential for efficient adhesion to intercellular adhesion molecule (ICAM) 1 and vascular cell adhesion molecule (VCAM) 1 and for proper trafficking of lymphocytes to secondary lymphoid organs. Interestingly, in RIAM-deficient mice, whereas peripheral lymph nodes (pLNs) were depleted of both B and T cells and recirculating B cells were diminished in the bone barrow (BM), the spleen was hypercellular, albeit with a relative deficiency of marginal zone B cells. The abnormality in lymphocyte trafficking was accompanied by defective humoral immunity to T-cell-dependent antigens. Platelet function was intact in RIAM-deficient animals. These in vivo results confirm a role for RIAM in the regulation of some, but not all, leukocyte integrins and suggest that RIAM-regulated integrin activation is required for trafficking of lymphocytes from blood into pLNs and BM, where relatively high shear forces exist in high endothelial venules and sinusoids, respectively.
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Dios-Esponera A, Isern de Val S, Sevilla-Movilla S, García-Verdugo R, García-Bernal D, Arellano-Sánchez N, Cabañas C, Teixidó J. Positive and negative regulation by SLP-76/ADAP and Pyk2 of chemokine-stimulated T-lymphocyte adhesion mediated by integrin α4β1. Mol Biol Cell 2015. [PMID: 26202465 PMCID: PMC4569313 DOI: 10.1091/mbc.e14-07-1246] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Stimulation by chemokines of integrin α4β1-dependent T-lymphocyte adhesion is a crucial step for lymphocyte trafficking. The adaptor Vav1 is required for chemokine-activated T-cell adhesion mediated by α4β1. Conceivably, proteins associating with Vav1 could potentially modulate this adhesion. Correlating with activation by the chemokine CXCL12 of T-lymphocyte attachment to α4β1 ligands, a transient stimulation in the association of Vav1 with SLP-76, Pyk2, and ADAP was observed. Using T-cells depleted for SLP-76, ADAP, or Pyk2, or expressing Pyk2 kinase-inactive forms, we show that SLP-76 and ADAP stimulate chemokine-activated, α4β1-mediated adhesion, whereas Pyk2 opposes T-cell attachment. While CXCL12-promoted generation of high-affinity α4β1 is independent of SLP-76, ADAP, and Pyk2, the strength of α4β1-VCAM-1 interaction and cell spreading on VCAM-1 are targets of regulation by these three proteins. GTPase assays, expression of activated or dominant-negative Rac1, or combined ADAP and Pyk2 silencing indicated that Rac1 activation by CXCL12 is a common mediator response in SLP-76-, ADAP-, and Pyk2-regulated cell adhesion involving α4β1. Our data strongly suggest that chemokine-stimulated associations between Vav1, SLP-76, and ADAP facilitate Rac1 activation and α4β1-mediated adhesion, whereas Pyk2 opposes this adhesion by limiting Rac1 activation.
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Affiliation(s)
- Ana Dios-Esponera
- Centro de Investigaciones Biológicas (CSIC), Department of Cellular and Molecular Medicine, 28040 Madrid, Spain
| | - Soledad Isern de Val
- Centro de Investigaciones Biológicas (CSIC), Department of Cellular and Molecular Medicine, 28040 Madrid, Spain
| | - Silvia Sevilla-Movilla
- Centro de Investigaciones Biológicas (CSIC), Department of Cellular and Molecular Medicine, 28040 Madrid, Spain
| | - Rosa García-Verdugo
- Centro de Investigaciones Biológicas (CSIC), Department of Cellular and Molecular Medicine, 28040 Madrid, Spain
| | - David García-Bernal
- Centro de Investigaciones Biológicas (CSIC), Department of Cellular and Molecular Medicine, 28040 Madrid, Spain
| | - Nohemí Arellano-Sánchez
- Centro de Investigaciones Biológicas (CSIC), Department of Cellular and Molecular Medicine, 28040 Madrid, Spain
| | - Carlos Cabañas
- Centro de Biología Molecular (CSIC), Department of Cell Biology and Immunology, Cantoblanco, 28049 Madrid, Spain
| | - Joaquin Teixidó
- Centro de Investigaciones Biológicas (CSIC), Department of Cellular and Molecular Medicine, 28040 Madrid, Spain
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Morrison VL, Uotila LM, Llort Asens M, Savinko T, Fagerholm SC. Optimal T Cell Activation and B Cell Antibody Responses In Vivo Require the Interaction between Leukocyte Function-Associated Antigen-1 and Kindlin-3. THE JOURNAL OF IMMUNOLOGY 2015; 195:105-15. [PMID: 25987740 DOI: 10.4049/jimmunol.1402741] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 04/21/2015] [Indexed: 12/29/2022]
Abstract
Kindlin-3 is an important integrin regulator that is mutated in the rare genetic disorder, leukocyte adhesion deficiency type III, a disorder characterized by defective neutrophil trafficking and platelet function, leading to recurrent bacterial infections and bleeding. Kindlin-3 is also known to regulate T cell adhesion in vitro and trafficking in vivo, but whether the integrin/kindlin interaction regulates T or B cell activation in vivo is unclear. In this study, we used TTT/AAA β2-integrin knock-in (KI) mice and TCR-transgenic (OT-II) KI mice, in which the integrin/kindlin connection is disrupted, to investigate the role of the integrin/kindlin interaction in T cell activation. We show that basal T cell activation status in these animals in vivo is normal, but they display reduced T cell activation by wild-type Ag-loaded dendritic cells in vitro. In addition, T cell activation in vivo is reduced. We also show that basal Ab levels are normal in TTT/AAA β2-integrin KI mice, but B cell numbers in lymph nodes and IgG and IgM production after immunization are reduced. In conclusion, we show that the integrin/kindlin interaction is required for trafficking of immune cells, as well as for T cell activation and B cell Ab responses in vivo. These results imply that the immunodeficiency found in leukocyte adhesion deficiency type III patients, in addition to being caused by defects in neutrophil function, may be due, in part, to defects in lymphocyte trafficking and activation.
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Affiliation(s)
| | - Liisa M Uotila
- Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland
| | - Marc Llort Asens
- Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland
| | - Terhi Savinko
- Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland
| | - Susanna Carola Fagerholm
- Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland; Medical Research Institute, University of Dundee, Dundee DD1 9SY, United Kingdom; and Faculty of Biological and Environmental Sciences, University of Helsinki, 00014 Helsinki, Finland
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50
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Yamashita-Kanemaru Y, Takahashi Y, Wang Y, Tahara-Hanaoka S, Honda SI, Bernhardt G, Shibuya A, Shibuya K. CD155 (PVR/Necl5) Mediates a Costimulatory Signal in CD4+ T Cells and Regulates Allergic Inflammation. THE JOURNAL OF IMMUNOLOGY 2015; 194:5644-53. [DOI: 10.4049/jimmunol.1401942] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Accepted: 04/20/2015] [Indexed: 12/21/2022]
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