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1
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Chen P, Chen J, Huang H, Liu W. Conventional dendritic cells are more activated in the hyperplastic Thymus of myasthenia gravis patients. J Neuroimmunol 2024; 395:578441. [PMID: 39216158 DOI: 10.1016/j.jneuroim.2024.578441] [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: 06/28/2024] [Revised: 08/12/2024] [Accepted: 08/19/2024] [Indexed: 09/04/2024]
Abstract
INTRODUCTION Dendritic cells (DCs) are crucial to form ectopic germinal centers (GCs) in the hyperplastic thymus (HT), which are typically found in anti-acetylcholine receptor autoantibody-positive myasthenia gravis (MG) patients. However, the characteristics of such DCs in the HT and their roles in thymic hyperplasia formation remain unclear. METHODS We collected thymic tissue from MG patients and patients who underwent cardiac surgery. The tissues were cut into sections for immunohistochemistry and immunofluorescence or digested into a single cell suspension for flow cytometry. RESULTS In addition to formation of ectopic GCs, we found that the proportion of the medulla in the thymic parenchyma was higher than that in the cortex (areacortex/areamedulla, 1.279 vs. 0.6576) in the HT of MG patients. The density of conventional dendritic cells (cDCs) in the HT was 131 ± 64.36 per mm2, whereas in normal thymic tissue, the density was 59.17 ± 22.54 per mm2. The more abundant cDCs expressed co-stimulatory molecules (CD80 and CD86) strongly. Moreover, the more abundant subset was mainly CD141+ DCs (cDC1s), accounting for an increase from 15% to 29%. However, these increased cDC1s appeared to be unrelated to Hassall's corpuscles and ectopic GCs. CONCLUSION Thymic hyperplasia in MG patients is manifested as an increase in the proportion of the thymic medulla accompanied by increases in the density and functional activation as well as changes in the subset composition of cDCs.
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Affiliation(s)
- Pei Chen
- Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, Guangzhou 510080, China; National Key Clinical Department and Key Discipline of Neurology, Guangzhou 510080, China.
| | - Jiaxin Chen
- Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, Guangzhou 510080, China; National Key Clinical Department and Key Discipline of Neurology, Guangzhou 510080, China
| | - Hao Huang
- Department of Neurology, The First People's Hospital of Nanning, Nanning 530022, China
| | - Weibin Liu
- Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, Guangzhou 510080, China; National Key Clinical Department and Key Discipline of Neurology, Guangzhou 510080, China.
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2
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Sado T, Cart JB, Lee CL. Mechanisms Underlying the Development of Murine T-Cell Lymphoblastic Lymphoma/Leukemia Induced by Total-Body Irradiation. Cancers (Basel) 2024; 16:2224. [PMID: 38927929 PMCID: PMC11201593 DOI: 10.3390/cancers16122224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 06/11/2024] [Accepted: 06/12/2024] [Indexed: 06/28/2024] Open
Abstract
Exposure to ionizing radiation is associated with an increased risk of hematologic malignancies in myeloid and lymphoid lineages in humans and experimental mice. Given that substantial evidence links radiation exposure with the risk of hematologic malignancies, it is imperative to deeply understand the mechanisms underlying cellular and molecular changes during the latency period between radiation exposure and the emergence of fully transformed malignant cells. One experimental model widely used in the field of radiation and cancer biology to study hematologic malignancies induced by radiation exposure is mouse models of radiation-induced thymic lymphoma. Murine radiation-induced thymic lymphoma is primarily driven by aberrant activation of Notch signaling, which occurs frequently in human precursor T-cell lymphoblastic lymphoma (T-LBL) and T-cell lymphoblastic leukemia (T-ALL). Here, we summarize the literature elucidating cell-autonomous and non-cell-autonomous mechanisms underlying cancer initiation, progression, and malignant transformation in the thymus following total-body irradiation (TBI) in mice.
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Affiliation(s)
- Toshihiko Sado
- National Institute of Radiological Sciences, Chiba 263-0024, Japan
| | - John B. Cart
- Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, USA
- Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Chang-Lung Lee
- Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27710, USA
- Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA
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3
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Shirafkan F, Hensel L, Rattay K. Immune tolerance and the prevention of autoimmune diseases essentially depend on thymic tissue homeostasis. Front Immunol 2024; 15:1339714. [PMID: 38571951 PMCID: PMC10987875 DOI: 10.3389/fimmu.2024.1339714] [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: 11/16/2023] [Accepted: 03/11/2024] [Indexed: 04/05/2024] Open
Abstract
The intricate balance of immune reactions towards invading pathogens and immune tolerance towards self is pivotal in preventing autoimmune diseases, with the thymus playing a central role in establishing and maintaining this equilibrium. The induction of central immune tolerance in the thymus involves the elimination of self-reactive T cells, a mechanism essential for averting autoimmunity. Disruption of the thymic T cell selection mechanisms can lead to the development of autoimmune diseases. In the dynamic microenvironment of the thymus, T cell migration and interactions with thymic stromal cells are critical for the selection processes that ensure self-tolerance. Thymic epithelial cells are particularly significant in this context, presenting self-antigens and inducing the negative selection of autoreactive T cells. Further, the synergistic roles of thymic fibroblasts, B cells, and dendritic cells in antigen presentation, selection and the development of regulatory T cells are pivotal in maintaining immune responses tightly regulated. This review article collates these insights, offering a comprehensive examination of the multifaceted role of thymic tissue homeostasis in the establishment of immune tolerance and its implications in the prevention of autoimmune diseases. Additionally, the developmental pathways of the thymus are explored, highlighting how genetic aberrations can disrupt thymic architecture and function, leading to autoimmune conditions. The impact of infections on immune tolerance is another critical area, with pathogens potentially triggering autoimmunity by altering thymic homeostasis. Overall, this review underscores the integral role of thymic tissue homeostasis in the prevention of autoimmune diseases, discussing insights into potential therapeutic strategies and examining putative avenues for future research on developing thymic-based therapies in treating and preventing autoimmune conditions.
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4
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Szafranska K, Sørensen KK, Lalor PF, McCourt P. Sinusoidal cells and liver immunology. SINUSOIDAL CELLS IN LIVER DISEASES 2024:53-75. [DOI: 10.1016/b978-0-323-95262-0.00003-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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5
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Shichkin VP, Antica M. Key Factors for Thymic Function and Development. Front Immunol 2022; 13:926516. [PMID: 35844535 PMCID: PMC9280625 DOI: 10.3389/fimmu.2022.926516] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 05/31/2022] [Indexed: 11/17/2022] Open
Abstract
The thymus is the organ responsible for T cell development and the formation of the adaptive immunity function. Its multicellular environment consists mainly of the different stromal cells and maturing T lymphocytes. Thymus-specific progenitors of epithelial, mesenchymal, and lymphoid cells with stem cell properties represent only minor populations. The thymic stromal structure predominantly determines the function of the thymus. The stromal components, mostly epithelial and mesenchymal cells, form this specialized area. They support the consistent developmental program of functionally distinct conventional T cell subpopulations. These include the MHC restricted single positive CD4+ CD8- and CD4- CD8+ cells, regulatory T lymphocytes (Foxp3+), innate natural killer T cells (iNKT), and γδT cells. Several physiological causes comprising stress and aging and medical treatments such as thymectomy and chemo/radiotherapy can harm the thymus function. The present review summarizes our knowledge of the development and function of the thymus with a focus on thymic epithelial cells as well as other stromal components and the signaling and transcriptional pathways underlying the thymic cell interaction. These critical thymus components are significant for T cell differentiation and restoring the thymic function after damage to reach the therapeutic benefits.
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6
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Vollmann EH, Rattay K, Barreiro O, Thiriot A, Fuhlbrigge RA, Vrbanac V, Kim KW, Jung S, Tager AM, von Andrian UH. Specialized transendothelial dendritic cells mediate thymic T-cell selection against blood-borne macromolecules. Nat Commun 2021; 12:6230. [PMID: 34711828 PMCID: PMC8553756 DOI: 10.1038/s41467-021-26446-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 09/27/2021] [Indexed: 12/29/2022] Open
Abstract
T cells undergo rigorous selection in the thymus to ensure self-tolerance and prevent autoimmunity, with this process requiring innocuous self-antigens (Ags) to be presented to thymocytes. Self-Ags are either expressed by thymic stroma cells or transported to the thymus from the periphery by migratory dendritic cells (DCs); meanwhile, small blood-borne peptides can access the thymic parenchyma by diffusing across the vascular lining. Here we describe an additional pathway of thymic Ag acquisition that enables circulating antigenic macromolecules to access both murine and human thymi. This pathway depends on a subset of thymus-resident DCs, distinct from both parenchymal and circulating migratory DCs, that are positioned in immediate proximity to thymic microvessels where they extend cellular processes across the endothelial barrier into the blood stream. Transendothelial positioning of DCs depends on DC-expressed CX3CR1 and its endothelial ligand, CX3CL1, and disrupting this chemokine pathway prevents thymic acquisition of circulating proteins and compromises negative selection of Ag-reactive thymocytes. Thus, transendothelial DCs represent a mechanism by which the thymus can actively acquire blood-borne Ags to induce and maintain central tolerance.
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Affiliation(s)
- Elisabeth H Vollmann
- Department of Immunology & HMS Center for Immune Imaging, Harvard Medical School, Boston, MA, 02115, USA
- Merck Research Laboratories, Boston, MA, 02115, USA
| | - Kristin Rattay
- Department of Immunology & HMS Center for Immune Imaging, Harvard Medical School, Boston, MA, 02115, USA
- Institute of Pharmacology, Biochemical Pharmacological Center, University of Marburg, Marburg, Germany
| | - Olga Barreiro
- Department of Immunology & HMS Center for Immune Imaging, Harvard Medical School, Boston, MA, 02115, USA
| | - Aude Thiriot
- Department of Immunology & HMS Center for Immune Imaging, Harvard Medical School, Boston, MA, 02115, USA
| | - Rebecca A Fuhlbrigge
- Department of Immunology & HMS Center for Immune Imaging, Harvard Medical School, Boston, MA, 02115, USA
| | - Vladimir Vrbanac
- Massachusetts General Hospital, Boston, MA, USA
- Massachusetts General Hospital, Humanized Immune System Mouse Program (HISMP), Boston, MA, 02114, USA
| | - Ki-Wook Kim
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
- Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL, 60612, USA
| | - Steffen Jung
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | | | - Ulrich H von Andrian
- Department of Immunology & HMS Center for Immune Imaging, Harvard Medical School, Boston, MA, 02115, USA.
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
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7
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Rothenberg EV. Single-cell insights into the hematopoietic generation of T-lymphocyte precursors in mouse and human. Exp Hematol 2021; 95:1-12. [PMID: 33454362 PMCID: PMC8018899 DOI: 10.1016/j.exphem.2020.12.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 12/23/2020] [Accepted: 12/24/2020] [Indexed: 01/29/2023]
Abstract
T-Cell development is a major branch of lymphoid development and a key output of hematopoiesis, especially in early life, but the molecular requirements for T-cell potential have remained obscure. Considerable advances have now been made toward solving this problem through single-cell transcriptome studies, interfaced with in vitro differentiation assays that monitor potential efficiently at the single-cell level. This review focuses on a series of recent reports studying mouse and human early T-cell precursors, both in the developing fetus and in stringently purified postnatal samples of intrathymic and prethymic T-lineage precursors. Cross-comparison of results reveals a robustly conserved core program in mouse and human, but with some informative and provocative variations between species and between ontogenic states. Repeated findings are the multipotent progenitor regulatory signature of thymus-seeding cells and the proximity of the T-cell program to dendritic cell programs, especially to plasmacytoid dendritic cells in humans.
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Affiliation(s)
- Ellen V Rothenberg
- Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA.
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8
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Environmental signals rather than layered ontogeny imprint the function of type 2 conventional dendritic cells in young and adult mice. Nat Commun 2021; 12:464. [PMID: 33469015 PMCID: PMC7815729 DOI: 10.1038/s41467-020-20659-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 12/13/2020] [Indexed: 01/29/2023] Open
Abstract
Conventional dendritic cells (cDC) are key activators of naive T cells, and can be targeted in adults to induce adaptive immunity, but in early life are considered under-developed or functionally immature. Here we show that, in early life, when the immune system develops, cDC2 exhibit a dual hematopoietic origin and, like other myeloid and lymphoid cells, develop in waves. Developmentally distinct cDC2 in early life, despite being distinguishable by fate mapping, are transcriptionally and functionally similar. cDC2 in early and adult life, however, are exposed to distinct cytokine environments that shape their transcriptional profile and alter their ability to sense pathogens, secrete cytokines and polarize T cells. We further show that cDC2 in early life, despite being distinct from cDC2 in adult life, are functionally competent and can induce T cell responses. Our results thus highlight the potential of harnessing cDC2 for boosting immunity in early life.
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9
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Deng Y, Chen H, Zeng Y, Wang K, Zhang H, Hu H. Leaving no one behind: tracing every human thymocyte by single-cell RNA-sequencing. Semin Immunopathol 2021; 43:29-43. [PMID: 33449155 DOI: 10.1007/s00281-020-00834-9] [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: 05/16/2020] [Accepted: 12/22/2020] [Indexed: 02/05/2023]
Abstract
The thymus is the primary organ for T-cell development, providing an essential microenvironment consisting of the appropriate cytokine milieu and specialized stromal cells. Thymus-seeding progenitors from circulation immigrate into the thymus and undergo the stepwise T-cell specification, commitment, and selection processes. The transcriptional factors, epigenetic regulators, and signaling pathways involved in the T-cell development have been intensively studied using mouse models. Despite our growing knowledge of T-cell development, major questions remain unanswered regarding the ontogeny and early events of T-cell development at the fetal stage, especially in humans. The recently developed single-cell RNA-sequencing technique provides an ideal tool to investigate the heterogeneity of T-cell precursors and the molecular mechanisms underlying the divergent fates of certain T-cell precursors at the single-cell level. In this review, we aim to summarize the current progress of the study on human thymus organogenesis and thymocyte and thymic epithelial cell development, which is to shed new lights on developing novel strategies for in vitro T-cell regeneration and thymus rejuvenation.
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Affiliation(s)
- Yujun Deng
- Department of Rheumatology and Immunology and State Key Laboratory of Biotherapy, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Hong Chen
- Department of Rheumatology and Immunology and State Key Laboratory of Biotherapy, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Yang Zeng
- State Key Laboratory of Experimental Hematology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100071, China.,State Key Laboratory of Proteomics, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing, 100071, China
| | - Keyue Wang
- Department of Rheumatology and Immunology and State Key Laboratory of Biotherapy, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Huiyuan Zhang
- Department of Rheumatology and Immunology and State Key Laboratory of Biotherapy, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
| | - Hongbo Hu
- Department of Rheumatology and Immunology and State Key Laboratory of Biotherapy, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
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10
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Naik SH. Dendritic cell development at a clonal level within a revised 'continuous' model of haematopoiesis. Mol Immunol 2020; 124:190-197. [PMID: 32593782 DOI: 10.1016/j.molimm.2020.06.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 04/15/2020] [Accepted: 06/11/2020] [Indexed: 12/17/2022]
Abstract
Understanding development of the dendritic cell (DC) subtypes continues to evolve. The origin and relationship of conventional DC type 1 (cDC1), cDC type 2 (cDC2) and plasmacytoid DCs (pDCs) to each other, and in relation to classic myeloid and lymphoid cells, has had a long and controversial history and is still not fully resolved. This review summarises the technological developments and findings that have been achieved at a clonal level, and how that has enhanced our knowledge of the process. It summarises the single cell lineage tracing technologies that have emerged, their application in in vitro and in vivo studies, in both mouse and human settings, and places the findings in a wider context of understanding haematopoiesis at a single cell or clonal level. In particular, it addresses the fate heterogeneity observed in many phenotypically defined progenitor subsets and how these findings have led to a departure from the classic ball-and-stick models of haematopoiesis to the emerging continuous model. Prior contradictions in DC development may be reconciled if they are framed within this revised model, where commitment to a lineage or cell type does not occur in an all-or-nothing process in defined progenitors but rather can occur at many stages of haematopoiesis in a dynamic process.
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Affiliation(s)
- Shalin H Naik
- Immunology Division, The Walter & Eliza Hall Institute of Medical Research, Parkville, Australia; The Department of Medical Biology, The University of Melbourne, Parkville, Australia.
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11
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Vongpipatana T, Nakahama T, Shibuya T, Kato Y, Kawahara Y. ADAR1 Regulates Early T Cell Development via MDA5-Dependent and -Independent Pathways. THE JOURNAL OF IMMUNOLOGY 2020; 204:2156-2168. [DOI: 10.4049/jimmunol.1900929] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 02/11/2020] [Indexed: 11/19/2022]
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12
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Shortman K. Dendritic cell development: A personal historical perspective. Mol Immunol 2020; 119:64-68. [PMID: 31986310 DOI: 10.1016/j.molimm.2019.12.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 12/02/2019] [Accepted: 12/20/2019] [Indexed: 01/01/2023]
Abstract
Dendritic cells(DCs) were once considered as a single cell type closely related developmentally to macrophages. Now we recognise several subtypes of DCs and have outlined several different pathways that potentially lead to their development. This article outlines some of the research findings that led to these changes in perspective, from the point of view of one of the participants.
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Affiliation(s)
- Ken Shortman
- The Walter and Eliza Hall Institute, Melbourne, Australia.
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13
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Tsaouli G, Barbarulo A, Vacca A, Screpanti I, Felli MP. Molecular Mechanisms of Notch Signaling in Lymphoid Cell Lineages Development: NF-κB and Beyond. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1227:145-164. [PMID: 32072504 DOI: 10.1007/978-3-030-36422-9_10] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Notch is a ligand-receptor interaction-triggered signaling cascade highly conserved, that influences multiple lineage decisions within the hematopoietic and the immune system. It is a recognized model of intercellular communication that plays an essential role in embryonic as well as in adult immune cell development and homeostasis. Four members belong to the family of Notch receptors (Notch1-4), and each of them plays nonredundant functions at several developmental stages. Canonical and noncanonical pathways of Notch signaling are multifaceted drivers of immune cells biology. In fact, increasing evidence highlighted Notch as an important modulator of immune responses, also in cancer microenvironment. In these contexts, multiple transduction signals, including canonical and alternative NF-κB pathways, play a relevant role. In this chapter, we will first describe the critical role of Notch and NF-κB signals in lymphoid lineages developing in thymus: natural killer T cells, thymocytes, and thymic T regulatory cells. We will address also the role played by ligand expressing cells. Given the importance of Notch/NF-κB cross talk, its role in T-cell leukemia development and progression will be discussed.
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Affiliation(s)
- G Tsaouli
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - A Barbarulo
- Department of Immunology, Institute of Immunity and Transplantation, Royal Free Hospital, London, UK
| | - A Vacca
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - I Screpanti
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
| | - M P Felli
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
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14
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Melnikov MV, Paschenkov MV, Boyko AN. [Dendritic cells in multiple sclerosis]. Zh Nevrol Psikhiatr Im S S Korsakova 2019; 117:22-30. [PMID: 28617358 DOI: 10.17116/jnevro20171172222-30] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Main functions, structure and stages of development of dendritic cells (DCs) are reviewed. A role of DCs in the development of immune tolerance and autoimmune diseases as well as involvement of DCs in the immunopathogenesis of multiple sclerosis (MS and their therapeutic potential in the treatment of MS are discussed.
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Affiliation(s)
- M V Melnikov
- Pirogov Russian National Research Medical University, Moscow, Russia
| | | | - A N Boyko
- Pirogov Russian National Research Medical University, Moscow, Russia; Moscow City Center of Multiple Sclerosis, Moscow, Russia
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15
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Ye Y, Kang X, Bailey J, Li C, Hong T. An enriched network motif family regulates multistep cell fate transitions with restricted reversibility. PLoS Comput Biol 2019; 15:e1006855. [PMID: 30845219 PMCID: PMC6424469 DOI: 10.1371/journal.pcbi.1006855] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Revised: 03/19/2019] [Accepted: 02/07/2019] [Indexed: 12/16/2022] Open
Abstract
Multistep cell fate transitions with stepwise changes of transcriptional profiles are common to many developmental, regenerative and pathological processes. The multiple intermediate cell lineage states can serve as differentiation checkpoints or branching points for channeling cells to more than one lineages. However, mechanisms underlying these transitions remain elusive. Here, we explored gene regulatory circuits that can generate multiple intermediate cellular states with stepwise modulations of transcription factors. With unbiased searching in the network topology space, we found a motif family containing a large set of networks can give rise to four attractors with the stepwise regulations of transcription factors, which limit the reversibility of three consecutive steps of the lineage transition. We found that there is an enrichment of these motifs in a transcriptional network controlling the early T cell development, and a mathematical model based on this network recapitulates multistep transitions in the early T cell lineage commitment. By calculating the energy landscape and minimum action paths for the T cell model, we quantified the stochastic dynamics of the critical factors in response to the differentiation signal with fluctuations. These results are in good agreement with experimental observations and they suggest the stable characteristics of the intermediate states in the T cell differentiation. These dynamical features may help to direct the cells to correct lineages during development. Our findings provide general design principles for multistep cell linage transitions and new insights into the early T cell development. The network motifs containing a large family of topologies can be useful for analyzing diverse biological systems with multistep transitions. The functions of cells are dynamically controlled in many biological processes including development, regeneration and disease progression. Cell fate transition, or the switch of cellular functions, often involves multiple steps. The intermediate stages of the transition provide the biological systems with the opportunities to regulate the transitions in a precise manner. These transitions are controlled by key regulatory genes of which the expression shows stepwise patterns, but how the interactions of these genes can determine the multistep processes was unclear. Here, we present a comprehensive analysis on the design principles of gene circuits that govern multistep cell fate transition. We found a large network family with common structural features that can generate systems with the ability to control three consecutive steps of the transition. We found that this type of networks is enriched in a gene circuit controlling the development of T lymphocyte, a crucial type of immune cells. We performed mathematical modeling using this gene circuit and we recapitulated the stepwise and irreversible loss of stem cell properties of the developing T lymphocytes. Our findings can be useful to analyze a wide range of gene regulatory networks controlling multistep cell fate transitions.
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Affiliation(s)
- Yujie Ye
- Department of Biochemistry & Cellular and Molecular Biology, The University of Tennessee, Knoxville, Tennessee, United States of America
| | - Xin Kang
- Shanghai Center for Mathematical Sciences, Fudan University, Shanghai, China.,School of Mathematical Sciences, Fudan University, Shanghai, China
| | - Jordan Bailey
- Department of Biochemistry & Cellular and Molecular Biology, The University of Tennessee, Knoxville, Tennessee, United States of America
| | - Chunhe Li
- Shanghai Center for Mathematical Sciences, Fudan University, Shanghai, China.,Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China
| | - Tian Hong
- Department of Biochemistry & Cellular and Molecular Biology, The University of Tennessee, Knoxville, Tennessee, United States of America.,National Institute for Mathematical and Biological Synthesis, Knoxville, Tennessee, United States of America
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16
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CECHIM GIOVANA, CHIES JOSÉA. In vitro generation of human monocyte-derived dendritic cells methodological aspects in a comprehensive review. ACTA ACUST UNITED AC 2019. [DOI: 10.1590/0001-3765201920190310] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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17
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Kratochvílová L, Sláma P. Overview of Bovine Dendritic Cells. ACTA UNIVERSITATIS AGRICULTURAE ET SILVICULTURAE MENDELIANAE BRUNENSIS 2018. [DOI: 10.11118/actaun201866030815] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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18
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Cosway EJ, Ohigashi I, Schauble K, Parnell SM, Jenkinson WE, Luther S, Takahama Y, Anderson G. Formation of the Intrathymic Dendritic Cell Pool Requires CCL21-Mediated Recruitment of CCR7 + Progenitors to the Thymus. THE JOURNAL OF IMMUNOLOGY 2018; 201:516-523. [PMID: 29784760 PMCID: PMC6036229 DOI: 10.4049/jimmunol.1800348] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 05/02/2018] [Indexed: 12/31/2022]
Abstract
During αβ T cell development in the thymus, migration of newly selected CD4+ and CD8+ thymocytes into medullary areas enables tolerance mechanisms to purge the newly selected αβ TCR repertoire of autoreactive specificities. Thymic dendritic cells (DC) play key roles in this process and consist of three distinct subsets that differ in their developmental origins. Thus, plasmacytoid DC and Sirpα+ conventional DC type 2 are extrathymically derived and enter into the thymus via their respective expression of the chemokine receptors CCR9 and CCR2. In contrast, although Sirpα− conventional DC type 1 (cDC1) are known to arise intrathymically from immature progenitors, the precise nature of such thymus-colonizing progenitors and the mechanisms controlling their thymus entry are unclear. In this article, we report a selective reduction in thymic cDC1 in mice lacking the chemokine receptor CCR7. In addition, we show that the thymus contains a CD11c+MHC class II−Sirpα−Flt3+ cDC progenitor population that expresses CCR7, and that migration of these cells to the thymus is impaired in Ccr7−/− mice. Moreover, thymic cDC1 defects in Ccr7−/− mice are mirrored in plt/plt mice, with further analysis of mice individually lacking the CCR7 ligands CCL21Ser (Ccl21a−/−) or CCL19 (Ccl19−/−) demonstrating an essential role for CCR7-CCL21Ser during intrathymic cDC1 development. Collectively, our data support a mechanism in which CCR7-CCL21Ser interactions guide the migration of cDC progenitors to the thymus for correct formation of the intrathymic cDC1 pool.
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Affiliation(s)
- Emilie J Cosway
- Institute for Immunology and Immunotherapy, Medical School, University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Izumi Ohigashi
- Division of Experimental Immunology, Institute of Advanced Medical Sciences, University of Tokushima, Tokushima 770-8503, Japan; and
| | - Karin Schauble
- Department of Biochemistry, Centre for Immunity and Infection Lausanne, University of Lausanne, 1066 Epalinges, Switzerland
| | - Sonia M Parnell
- Institute for Immunology and Immunotherapy, Medical School, University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - William E Jenkinson
- Institute for Immunology and Immunotherapy, Medical School, University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Sanjiv Luther
- Department of Biochemistry, Centre for Immunity and Infection Lausanne, University of Lausanne, 1066 Epalinges, Switzerland
| | - Yousuke Takahama
- Division of Experimental Immunology, Institute of Advanced Medical Sciences, University of Tokushima, Tokushima 770-8503, Japan; and
| | - Graham Anderson
- Institute for Immunology and Immunotherapy, Medical School, University of Birmingham, Birmingham B15 2TT, United Kingdom;
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19
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Salvermoser J, van Blijswijk J, Papaioannou NE, Rambichler S, Pasztoi M, Pakalniškytė D, Rogers NC, Keppler SJ, Straub T, Reis e Sousa C, Schraml BU. Clec9a-Mediated Ablation of Conventional Dendritic Cells Suggests a Lymphoid Path to Generating Dendritic Cells In Vivo. Front Immunol 2018; 9:699. [PMID: 29713321 PMCID: PMC5911463 DOI: 10.3389/fimmu.2018.00699] [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: 02/07/2018] [Accepted: 03/21/2018] [Indexed: 01/01/2023] Open
Abstract
Conventional dendritic cells (cDCs) are versatile activators of immune responses that develop as part of the myeloid lineage downstream of hematopoietic stem cells. We have recently shown that in mice precursors of cDCs, but not of other leukocytes, are marked by expression of DNGR-1/CLEC9A. To genetically deplete DNGR-1-expressing cDC precursors and their progeny, we crossed Clec9a-Cre mice to Rosa-lox-STOP-lox-diphtheria toxin (DTA) mice. These mice develop signs of age-dependent myeloproliferative disease, as has been observed in other DC-deficient mouse models. However, despite efficient depletion of cDC progenitors in these mice, cells with phenotypic characteristics of cDCs populate the spleen. These cells are functionally and transcriptionally similar to cDCs in wild type control mice but show somatic rearrangements of Ig-heavy chain genes, characteristic of lymphoid origin cells. Our studies reveal a previously unappreciated developmental heterogeneity of cDCs and suggest that the lymphoid lineage can generate cells with features of cDCs when myeloid cDC progenitors are impaired.
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Affiliation(s)
- Johanna Salvermoser
- Walter-Brendel-Centre for Experimental Medicine, University Hospital, LMU Munich, Planegg Martinsried, Germany.,Biomedical Center, LMU Munich, Planegg Martinsried, Germany
| | | | | | - Stephan Rambichler
- Walter-Brendel-Centre for Experimental Medicine, University Hospital, LMU Munich, Planegg Martinsried, Germany.,Biomedical Center, LMU Munich, Planegg Martinsried, Germany
| | - Maria Pasztoi
- Biomedical Center, LMU Munich, Planegg Martinsried, Germany
| | - Dalia Pakalniškytė
- Walter-Brendel-Centre for Experimental Medicine, University Hospital, LMU Munich, Planegg Martinsried, Germany.,Biomedical Center, LMU Munich, Planegg Martinsried, Germany
| | - Neil C Rogers
- Immunobiology Laboratory, The Francis Crick Institute, London, United Kingdom
| | - Selina J Keppler
- Technische Universität München, Klinikum Rechts der Isar, Institut für Klinische Chemie und Pathobiochemie, Munich, Germany
| | - Tobias Straub
- Biomedical Center, LMU Munich, Planegg Martinsried, Germany.,Core Facility Bioinformatics, Biomedical Center (BMC), LMU Munich, Planegg Martinsried, Germany
| | | | - Barbara U Schraml
- Walter-Brendel-Centre for Experimental Medicine, University Hospital, LMU Munich, Planegg Martinsried, Germany.,Biomedical Center, LMU Munich, Planegg Martinsried, Germany
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20
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Oh J, Wu N, Barczak AJ, Barbeau R, Erle DJ, Shin JS. CD40 Mediates Maturation of Thymic Dendritic Cells Driven by Self-Reactive CD4 + Thymocytes and Supports Development of Natural Regulatory T Cells. THE JOURNAL OF IMMUNOLOGY 2018; 200:1399-1412. [PMID: 29321275 DOI: 10.4049/jimmunol.1700768] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Accepted: 12/13/2017] [Indexed: 01/22/2023]
Abstract
Thymic dendritic cells (tDCs) play an important role in central tolerance by eliminating self-reactive thymocytes or differentiating them to regulatory T (Treg) cells. However, the molecular and cellular mechanisms underlying these functions are not completely understood. We found that mouse tDCs undergo maturation following cognate interaction with self-reactive CD4+ thymocytes and that this maturation is dependent on CD40 signaling. Ablation of CD40 expression in tDCs resulted in a significant reduction in the number of Treg cells in association with a significant reduction in the number of mature tDCs. In addition, CD40-deficient DCs failed to fully mature upon cognate interaction with CD4+ thymocytes in vitro and failed to differentiate them into Treg cells to a sufficient number. These findings suggest that tDCs mature and potentiate Treg cell development in feedback response to self-reactive CD4+ thymocytes.
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Affiliation(s)
- Jaehak Oh
- Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, CA 94143; and
| | - Nan Wu
- Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, CA 94143; and
| | - Andrea J Barczak
- Department of Medicine, Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, CA 94143
| | - Rebecca Barbeau
- Department of Medicine, Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, CA 94143
| | - David J Erle
- Department of Medicine, Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, CA 94143
| | - Jeoung-Sook Shin
- Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, CA 94143; and
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21
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Cédile O, Jørgensen LØ, Frank I, Wlodarczyk A, Owens T. The chemokine receptor CCR2 maintains plasmacytoid dendritic cell homeostasis. Immunol Lett 2017; 192:72-78. [DOI: 10.1016/j.imlet.2017.10.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 09/04/2017] [Accepted: 10/24/2017] [Indexed: 12/24/2022]
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22
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Martín-Gayo E, González-García S, García-León MJ, Murcia-Ceballos A, Alcain J, García-Peydró M, Allende L, de Andrés B, Gaspar ML, Toribio ML. Spatially restricted JAG1-Notch signaling in human thymus provides suitable DC developmental niches. J Exp Med 2017; 214:3361-3379. [PMID: 28947612 PMCID: PMC5679173 DOI: 10.1084/jem.20161564] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 06/18/2017] [Accepted: 08/08/2017] [Indexed: 01/06/2023] Open
Abstract
Martín-Gayo et al. report that human early thymic progenitors can undergo a GATA2-dependent myeloid developmental program leading to resident dendritic cells (DCs) upon JAG1-Notch activation. The identification of JAG1+ DC-permissive intrathymic niches validates the human thymus as a DC-poietic organ. A key unsolved question regarding the developmental origin of conventional and plasmacytoid dendritic cells (cDCs and pDCs, respectively) resident in the steady-state thymus is whether early thymic progenitors (ETPs) could escape T cell fate constraints imposed normally by a Notch-inductive microenvironment and undergo DC development. By modeling DC generation in bulk and clonal cultures, we show here that Jagged1 (JAG1)-mediated Notch signaling allows human ETPs to undertake a myeloid transcriptional program, resulting in GATA2-dependent generation of CD34+ CD123+ progenitors with restricted pDC, cDC, and monocyte potential, whereas Delta-like1 signaling down-regulates GATA2 and impairs myeloid development. Progressive commitment to the DC lineage also occurs intrathymically, as myeloid-primed CD123+ monocyte/DC and common DC progenitors, equivalent to those previously identified in the bone marrow, are resident in the normal human thymus. The identification of a discrete JAG1+ thymic medullary niche enriched for DC-lineage cells expressing Notch receptors further validates the human thymus as a DC-poietic organ, which provides selective microenvironments permissive for DC development.
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Affiliation(s)
- Enrique Martín-Gayo
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
| | - Sara González-García
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
| | - María J García-León
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
| | - Alba Murcia-Ceballos
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
| | - Juan Alcain
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
| | - Marina García-Peydró
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
| | - Luis Allende
- Immunology Department, i+12 Research Institute, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Belén de Andrés
- Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain
| | - María L Gaspar
- Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain
| | - María L Toribio
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
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23
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Zhao HM, Han F, Xu R, Huang XY, Cheng SM, Huang MF, Yue HY, Wang X, Zou Y, Xu HL, Liu DY. Therapeutic effect of curcumin on experimental colitis mediated by inhibiting CD8 +CD11c + cells. World J Gastroenterol 2017; 23:1804-1815. [PMID: 28348486 PMCID: PMC5352921 DOI: 10.3748/wjg.v23.i10.1804] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2016] [Revised: 12/25/2016] [Accepted: 01/17/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To verify whether curcumin (Cur) can treat inflammatory bowel disease by regulating CD8+CD11c+ cells.
METHODS We evaluated the suppressive effect of Cur on CD8+CD11c+ cells in spleen and Peyer’s patches (PPs) in colitis induced by trinitrobenzene sulfonic acid. Mice with colitis were treated by 200 mg/kg Cur for 7 d. On day 8, the therapeutic effect of Cur was evaluated by visual assessment and histological examination, while co-stimulatory molecules of CD8+CD11c+ cells in the spleen and PPs were measured by flow cytometry. The levels of interleukin (IL)-10, interferon (IFN)-γ and transforming growth factor (TGF)-β1 in spleen and colonic mucosa were determined by ELISA.
RESULTS The disease activity index, colon weight, weight index of colon and histological score of experimental colitis were obviously decreased after Cur treatment, while the body weight and colon length recovered. After treatment with Cur, CD8+CD11c+ cells were decreased in the spleen and PPs, and the expression of major histocompatibility complex II, CD205, CD40, CD40L and intercellular adhesion molecule-1 was inhibited. IL-10, IFN-γ and TGF-β1 levels were increased compared with those in mice with untreated colitis.
CONCLUSION Cur can effectively treat experimental colitis, which is realized by inhibiting CD8+CD11c+ cells.
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24
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Keselowsky BG, Lewis JS. Dendritic cells in the host response to implanted materials. Semin Immunol 2017; 29:33-40. [PMID: 28487131 PMCID: PMC5612375 DOI: 10.1016/j.smim.2017.04.002] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 03/29/2017] [Accepted: 04/18/2017] [Indexed: 12/28/2022]
Abstract
The role of dendritic cells (DCs) and their targeted manipulation in the body's response to implanted materials is an important and developing area of investigation, and a large component of the emerging field of biomaterials-based immune engineering. The key position of DCs in the immune system, serving to bridge innate and adaptive immunity, is facilitated by rich diversity in type and function and places DCs as a critical mediator to biomaterials of both synthetic and natural origins. This review presents current views regarding DC biology and summarizes recent findings in DC responses to implanted biomaterials. Based on these findings, there is promise that the directed programming of application-specific DC responses to biomaterials can become a reality, enabling and enhancing applications almost as diverse as the larger field of biomaterials itself.
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Affiliation(s)
- Benjamin G Keselowsky
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611 USA.
| | - Jamal S Lewis
- Department of Biomedical Engineering, University of California, Davis, CA 95616, USA
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25
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Xu Y, Jiang D, Hu Y, Li Y, Zhang X, Wang J, Wang Y. Fms-like tyrosine kinase 3 ligand is required for thymic dendritic cell generation from bone marrow-derived CD117⁺ hematopoietic progenitor cells. Mol Med Rep 2015; 12:6969-75. [PMID: 26397863 DOI: 10.3892/mmr.2015.4320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Accepted: 08/17/2015] [Indexed: 11/06/2022] Open
Abstract
Thymic dendritic cells (TDCs) are a type of dendritic cell (DC) in the thymus, which can enhance the proliferation of thymic T lymphocytes, regulate negative selection and induce central tolerance through autoantigen presentation. However, further investigations using TDCs has been restricted due to insufficient numbers. Therefore, an effective expansion method for TDCs in vitro is urgently required to further examine their biological characteristics. In the present study, a novel system was established using fetal thymus organ culture (FTOC) and a hanging drop culture system in the presence of fms‑like tyrosine kinase 3 ligand (Flt3L), termed the Flt3L/FTOC system. TDCs were successfully generated and expanded from CD117+ bone marrow hematopoietic progenitor cells. Conventional DCs (cDCs; CD11c+B220‑ DCs) and plasmacytoid DCs (pDCs; CD11c+B220+ DCs) were found in the TDCs generated using the Flt3L/FTOC system. These cells exhibited the specific morphological features of DCs, which were confirmed using Giemsa staining. Furthermore, the cytokine and surface marker profiles were also analyzed. Higher expression levels of interferon‑α and interleukin‑12 were observed in the pDCs, compared with the cDCs, and higher expression levels of toll‑like receptor (TLR)7 and TLR9 were found in the pDCs than in the cDCs. In addition, the Flt3L/FTOC‑derived TDCs also exhibited the ability to stimulate the allogenic T cell response. In conclusion, a novel in vitro culture system of thymic cDCs and pDCs using Flt3L was established, and this may provide a methodological basis for understanding the properties of TDCs.
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Affiliation(s)
- Yunyun Xu
- Institute of Pediatrics, Children's Hospital Affiliated to Soochow University Suzhou, Jiangsu 215025, P.R. China
| | - Dong Jiang
- Stem Cell and Biomedical Material Key Laboratory of Jiangsu Province, State Key Laboratory Incubation Base, Soochow University, Suzhou, Jiangsu 215007, P.R. China
| | - Yizhou Hu
- Department of Virology, The Haartman Institute, Molecular Cancer Biology Research Program and Helsinki University Hospital, University of Helsinki, Helsinki FIN‑00100, Finland
| | - Yiping Li
- Institute of Pediatrics, Children's Hospital Affiliated to Soochow University Suzhou, Jiangsu 215025, P.R. China
| | - Xueguang Zhang
- Stem Cell and Biomedical Material Key Laboratory of Jiangsu Province, State Key Laboratory Incubation Base, Soochow University, Suzhou, Jiangsu 215007, P.R. China
| | - Jian Wang
- Institute of Pediatrics, Children's Hospital Affiliated to Soochow University Suzhou, Jiangsu 215025, P.R. China
| | - Yong Wang
- Department of Medicine, Division of Pulmonary Allergy and Critical Care Medicine, University of Alabama, Birmingham, AL 35233, USA
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26
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Lopes N, Sergé A, Ferrier P, Irla M. Thymic Crosstalk Coordinates Medulla Organization and T-Cell Tolerance Induction. Front Immunol 2015; 6:365. [PMID: 26257733 PMCID: PMC4507079 DOI: 10.3389/fimmu.2015.00365] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Accepted: 07/06/2015] [Indexed: 12/29/2022] Open
Abstract
The thymus ensures the generation of a functional and highly diverse T-cell repertoire. The thymic medulla, which is mainly composed of medullary thymic epithelial cells (mTECs) and dendritic cells (DCs), provides a specialized microenvironment dedicated to the establishment of T-cell tolerance. mTECs play a privileged role in this pivotal process by their unique capacity to express a broad range of peripheral self-antigens that are presented to developing T cells. Reciprocally, developing T cells control mTEC differentiation and organization. These bidirectional interactions are commonly referred to as thymic crosstalk. This review focuses on the relative contributions of mTEC and DC subsets to the deletion of autoreactive T cells and the generation of natural regulatory T cells. We also summarize current knowledge regarding how hematopoietic cells conversely control the composition and complex three-dimensional organization of the thymic medulla.
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Affiliation(s)
- Noëlla Lopes
- Centre d'Immunologie de Marseille-Luminy, INSERM, U1104, CNRS UMR7280, Aix-Marseille Université UM2 , Marseille , France
| | - Arnauld Sergé
- Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, INSERM U1068, CNRS UMR7258, Aix-Marseille Université UM105 , Marseille , France
| | - Pierre Ferrier
- Centre d'Immunologie de Marseille-Luminy, INSERM, U1104, CNRS UMR7280, Aix-Marseille Université UM2 , Marseille , France
| | - Magali Irla
- Centre d'Immunologie de Marseille-Luminy, INSERM, U1104, CNRS UMR7280, Aix-Marseille Université UM2 , Marseille , France
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27
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Oh J, Shin JS. The Role of Dendritic Cells in Central Tolerance. Immune Netw 2015; 15:111-20. [PMID: 26140042 PMCID: PMC4486773 DOI: 10.4110/in.2015.15.3.111] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Revised: 05/26/2015] [Accepted: 06/02/2015] [Indexed: 12/16/2022] Open
Abstract
Dendritic cells (DCs) play a significant role in establishing self-tolerance through their ability to present self-antigens to developing T cells in the thymus. DCs are predominantly localized in the medullary region of thymus and present a broad range of self-antigens, which include tissue-restricted antigens expressed and transferred from medullary thymic epithelial cells, circulating antigens directly captured by thymic DCs through coticomedullary junction blood vessels, and peripheral tissue antigens captured and transported by peripheral tissue DCs homing to the thymus. When antigen-presenting DCs make a high affinity interaction with antigen-specific thymocytes, this interaction drives the interacting thymocytes to death, a process often referred to as negative selection, which fundamentally blocks the self-reactive thymocytes from differentiating into mature T cells. Alternatively, the interacting thymocytes differentiate into the regulatory T (Treg) cells, a distinct T cell subset with potent immune suppressive activities. The specific mechanisms by which thymic DCs differentiate Treg cells have been proposed by several laboratories. Here, we review the literatures that elucidate the contribution of thymic DCs to negative selection and Treg cell differentiation, and discusses its potential mechanisms and future directions.
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Affiliation(s)
- Jaehak Oh
- Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, CA 94143, USA
| | - Jeoung-Sook Shin
- Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, CA 94143, USA
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28
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Vremec D, Shortman K. What's in a Name? Some Early and Current Issues in Dendritic Cell Nomenclature. Front Immunol 2015; 6:267. [PMID: 26074925 PMCID: PMC4448511 DOI: 10.3389/fimmu.2015.00267] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Accepted: 05/14/2015] [Indexed: 11/18/2022] Open
Affiliation(s)
- David Vremec
- The Walter and Eliza Hall Institute , Melbourne, VIC , Australia
| | - Ken Shortman
- The Walter and Eliza Hall Institute , Melbourne, VIC , Australia ; Department of Medical Biology, The University of Melbourne , Melbourne, VIC , Australia ; Burnet Institute , Melbourne, VIC , Australia
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29
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Abstract
The lymphocyte family has expanded significantly in recent years to include not only the adaptive lymphocytes (T cells, B cells) and NK cells, but also several additional innate lymphoid cell (ILC) types. ILCs lack clonally distributed antigen receptors characteristic of adaptive lymphocytes and instead respond exclusively to signaling via germline-encoded receptors. ILCs resemble T cells more closely than any other leukocyte lineage at the transcriptome level and express many elements of the core T cell transcriptional program, including Notch, Gata3, Tcf7, and Bcl11b. We present our current understanding of the shared and distinct transcriptional regulatory mechanisms involved in the development of adaptive T lymphocytes and closely related ILCs. We discuss the possibility that a core set of transcriptional regulators common to ILCs and T cells establish enhancers that enable implementation of closely aligned effector pathways. Studies of the transcriptional regulation of lymphopoiesis will support the development of novel therapeutic approaches to correct early lymphoid developmental defects and aberrant lymphocyte function.
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Affiliation(s)
- Maria Elena De Obaldia
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104
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30
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Limited niche availability suppresses murine intrathymic dendritic-cell development from noncommitted progenitors. Blood 2014; 125:457-64. [PMID: 25411428 DOI: 10.1182/blood-2014-07-592667] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
The origins of dendritic cells (DCs) and other myeloid cells in the thymus have remained controversial. In this study, we assessed developmental relationships between thymic dendritic cells and thymocytes, employing retrovirus-based cellular barcoding and reporter mice, as well as intrathymic transfers coupled with DC depletion. We demonstrated that a subset of early T-lineage progenitors expressed CX3CR1, a bona fide marker for DC progenitors. However, intrathymic transfers into nonmanipulated mice, as well as retroviral barcoding, indicated that thymic dendritic cells and thymocytes were largely of distinct developmental origin. In contrast, intrathymic transfers after in vivo depletion of DCs resulted in intrathymic development of non-T-lineage cells. In conclusion, our data support a model in which the adoption of T-lineage fate by noncommitted progenitors at steady state is enforced by signals from the thymic microenvironment unless niches promoting alternative lineage fates become available.
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31
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Abstract
Classical dendritic cells (cDCs) form a critical interface between innate and adaptive immunity. As myeloid immune cell sentinels, cDCs are specialized in the sensing of pathogen challenges and cancer. They translate the latter for T cells into peptide form. Moreover, cDCs provide additional critical information on the original antigen context to trigger a diverse spectrum of appropriate protective responses. Here we review recent progress in our understanding of cDC subsets in mice. We will discuss cDC subset ontogeny and transcription factor dependencies, as well as emerging functional specializations within the cDC compartment in lymphoid and nonlymphoid tissues.
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Affiliation(s)
- Alexander Mildner
- Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Steffen Jung
- Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
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32
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Kyoizumi S, Kubo Y, Kajimura J, Yoshida K, Hayashi T, Nakachi K, Young LF, Moore MA, van den Brink MRM, Kusunoki Y. Linkage between dendritic and T cell commitments in human circulating hematopoietic progenitors. THE JOURNAL OF IMMUNOLOGY 2014; 192:5749-60. [PMID: 24835400 DOI: 10.4049/jimmunol.1303260] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The relationships between commitments of dendritic cells (DCs) and T cells in human hematopoietic stem cells are not well understood. In this study, we enumerate and characterize conventional DC and plasmacytoid DC precursors in association with T cell and thymus-derived types of NK cell precursors among CD34(+) hematopoietic progenitor cells (HPCs) circulating in human peripheral blood. By limiting-dilution analyses using coculture with stroma cells expressing Notch1 ligand, the precursor frequencies (PFs) of DCs in HPCs were found to significantly correlate with T cell PFs, but not with NK cell PFs, among healthy donors. Clonal analyses showed that the majority of T/NK dual- and T single-lineage precursors-but only a minority of NK single-lineage precursors-were associated with the generation of DC progenies. All clones producing both DC and T cell progenies were found with monocyte and/or granulocyte progenies, suggesting DC differentiation via myeloid DC pathways. Analyses of peripheral blood HPC subpopulations revealed that the lineage split between DC and T/NK cell progenitor occurs at the stage prior to bifurcation into T and NK cell lineages. The findings suggest a strong linkage between DC and T cell commitments, which may be imprinted in circulating lymphoid-primed multipotent progenitors or in more upstream HPCs.
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Affiliation(s)
- Seishi Kyoizumi
- Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hiroshima 732-0815, Japan;
| | - Yoshiko Kubo
- Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hiroshima 732-0815, Japan
| | - Junko Kajimura
- Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hiroshima 732-0815, Japan
| | - Kengo Yoshida
- Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hiroshima 732-0815, Japan
| | - Tomonori Hayashi
- Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hiroshima 732-0815, Japan
| | - Kei Nakachi
- Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hiroshima 732-0815, Japan
| | - Lauren F Young
- Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065; and
| | - Malcolm A Moore
- Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065
| | - Marcel R M van den Brink
- Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065; and
| | - Yoichiro Kusunoki
- Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hiroshima 732-0815, Japan
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33
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Paul F, Amit I. Plasticity in the transcriptional and epigenetic circuits regulating dendritic cell lineage specification and function. Curr Opin Immunol 2014; 30:1-8. [PMID: 24820527 DOI: 10.1016/j.coi.2014.04.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2014] [Accepted: 04/09/2014] [Indexed: 12/23/2022]
Abstract
Dendritic cells (DC) are critical and functionally versatile innate immune sentinels. Here, we coarsely partition the adult DC lineage into three developmental subtypes and argue that pioneer transcription factors and chromatin remodeling are responsible for specification and plasticity between the DC subsets. Subsequently, intricate signaling-dependent transcription factor networks generate different functional states in response to pathogen stimuli within a specified DC subtype. To expand our understanding of lineage heterogeneity and functional activation states, we discuss the use of single cell genomics approaches in the context of a newly emerging systems immunology era, complementing the dichotomous definition of immune cells based solely on their surface marker expression. Rapid developments in single cell genomics are beginning to provide us with robust tools to potentially revise the working models of DC specification and the common hematopoietic tree.
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Affiliation(s)
- Franziska Paul
- Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Ido Amit
- Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
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34
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Rezzani R, Nardo L, Favero G, Peroni M, Rodella LF. Thymus and aging: morphological, radiological, and functional overview. AGE (DORDRECHT, NETHERLANDS) 2014; 36:313-51. [PMID: 23877171 PMCID: PMC3889907 DOI: 10.1007/s11357-013-9564-5] [Citation(s) in RCA: 113] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Accepted: 07/01/2013] [Indexed: 05/20/2023]
Abstract
Aging is a continuous process that induces many alterations in the cytoarchitecture of different organs and systems both in humans and animals. Moreover, it is associated with increased susceptibility to infectious, autoimmune, and neoplastic processes. The thymus is a primary lymphoid organ responsible for the production of immunocompetent T cells and, with aging, it atrophies and declines in functions. Universality of thymic involution in all species possessing thymus, including human, indicates it as a long-standing evolutionary event. Although it is accepted that many factors contribute to age-associated thymic involution, little is known about the mechanisms involved in the process. The exact time point of the initiation is not well defined. To address the issue, we report the exact age of thymus throughout the review so that readers can have a nicely pictured synoptic view of the process. Focusing our attention on the different stages of the development of the thymus gland (natal, postnatal, adult, and old), we describe chronologically the morphological changes of the gland. We report that the thymic morphology and cell types are evolutionarily preserved in several vertebrate species. This finding is important in understanding the similar problems caused by senescence and other diseases. Another point that we considered very important is to indicate the assessment of the thymus through radiological images to highlight its variability in shape, size, and anatomical conformation.
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Affiliation(s)
- Rita Rezzani
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, Viale Europa 11, 25123, Brescia, Italy,
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35
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De Obaldia ME, Bell JJ, Wang X, Harly C, Yashiro-Ohtani Y, DeLong JH, Zlotoff DA, Sultana DA, Pear WS, Bhandoola A. T cell development requires constraint of the myeloid regulator C/EBP-α by the Notch target and transcriptional repressor Hes1. Nat Immunol 2013; 14:1277-84. [PMID: 24185616 DOI: 10.1038/ni.2760] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2013] [Accepted: 10/07/2013] [Indexed: 12/12/2022]
Abstract
Notch signaling induces gene expression of the T cell lineage and discourages alternative fate outcomes. Hematopoietic deficiency in the Notch target Hes1 results in severe T cell lineage defects; however, the underlying mechanism is unknown. We found here that Hes1 constrained myeloid gene-expression programs in T cell progenitor cells, as deletion of the myeloid regulator C/EBP-α restored the development of T cells from Hes1-deficient progenitor cells. Repression of Cebpa by Hes1 required its DNA-binding and Groucho-recruitment domains. Hes1-deficient multipotent progenitor cells showed a developmental bias toward myeloid cells and dendritic cells after Notch signaling, whereas Hes1-deficient lymphoid progenitor cells required additional cytokine signaling for diversion into the myeloid lineage. Our findings establish the importance of constraining developmental programs of the myeloid lineage early in T cell development.
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Affiliation(s)
- Maria Elena De Obaldia
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
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36
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Merad M, Sathe P, Helft J, Miller J, Mortha A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol 2013; 31:563-604. [PMID: 23516985 DOI: 10.1146/annurev-immunol-020711-074950] [Citation(s) in RCA: 1750] [Impact Index Per Article: 145.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Dendritic cells (DCs) form a remarkable cellular network that shapes adaptive immune responses according to peripheral cues. After four decades of research, we now know that DCs arise from a hematopoietic lineage distinct from other leukocytes, establishing the DC system as a unique hematopoietic branch. Recent work has also established that tissue DCs consist of developmentally and functionally distinct subsets that differentially regulate T lymphocyte function. This review discusses major advances in our understanding of the regulation of DC lineage commitment, differentiation, diversification, and function in situ.
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Affiliation(s)
- Miriam Merad
- Department of Oncological Sciences, Mount Sinai Medical School, New York, NY 10029, USA.
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37
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Hadeiba H, Butcher EC. Thymus-homing dendritic cells in central tolerance. Eur J Immunol 2013; 43:1425-9. [PMID: 23616226 PMCID: PMC3774955 DOI: 10.1002/eji.201243192] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2012] [Revised: 04/18/2013] [Accepted: 04/18/2013] [Indexed: 12/31/2022]
Abstract
Central tolerance is critical in establishing a peripheral T-cell repertoire purged of functional autoreactive T cells. One of the major requirements for effective central tolerance is the presentation of self and other innocuous antigens (Ags), including food, gut flora, or airway allergens, to developing T cells in the thymus. This seemingly challenging task can be mediated in some cases by ectopic expression of tissue-specific Ags by thymic epithelial cells or by entry of systemic blood-borne Ags into the thymus. More recently, thymic homing peripheral dendritic cells (DCs) have been proposed as cellular transporters of peripheral tissue-specific Ags or foreign innocuous Ags. The aim of this viewpoint is to discuss the three principal thymic DC populations and their trafficking properties in the context of central tolerance. We will first discuss the importance of peripheral DC trafficking to the thymus and then compare and contrast the three DC subsets. We will describe how they were characterized, describe their trafficking to and their microenvironmental positioning in the thymus, and discuss the functional consequence of thymic trafficking and localization on thymic selection events.
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Affiliation(s)
- Husein Hadeiba
- Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
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38
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Moore AJ, Anderson MK. Dendritic cell development: a choose-your-own-adventure story. Adv Hematol 2013; 2013:949513. [PMID: 23476654 PMCID: PMC3588201 DOI: 10.1155/2013/949513] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2012] [Accepted: 12/27/2012] [Indexed: 12/13/2022] Open
Abstract
Dendritic cells (DCs) are essential components of the immune system and contribute to immune responses by activating or tolerizing T cells. DCs comprise a heterogeneous mixture of subsets that are located throughout the body and possess distinct and specialized functions. Although numerous defined precursors from the bone marrow and spleen have been identified, emerging data in the field suggests many alternative routes of DC differentiation from precursors with multilineage potential. Here, we discuss how the combinatorial expression of transcription factors can promote one DC lineage over another as well as the integration of cytokine signaling in this process.
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Affiliation(s)
- Amanda J. Moore
- Division of Biological Sciences, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON, Canada M4N 3M5
- Department of Immunology, University of Toronto, Toronto, ON, Canada M5S 1A8
| | - Michele K. Anderson
- Division of Biological Sciences, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON, Canada M4N 3M5
- Department of Immunology, University of Toronto, Toronto, ON, Canada M5S 1A8
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39
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Guerri L, Peguillet I, Geraldo Y, Nabti S, Premel V, Lantz O. Analysis of APC types involved in CD4 tolerance and regulatory T cell generation using reaggregated thymic organ cultures. THE JOURNAL OF IMMUNOLOGY 2013; 190:2102-10. [PMID: 23365074 DOI: 10.4049/jimmunol.1202883] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Tolerance to self-Ags is generated in the thymus. Both epithelial and hematopoietic thymic stromal cells play an active and essential role in this process. However, the role of each of the various stromal cell types remains unresolved. To our knowledge, we describe the first comparative analysis of several types of thymic hematopoietic stromal cells (THSCs) for their ability to induce CD4 tolerance to self, in parallel with the thymic epithelium. The THSCs--two types of conventional dendritic cells (cDCs), plasmacytoid dendritic cells, macrophages (MΦs), B lymphocytes, and eosinophils--were first characterized and quantified in adult mouse thymus. They were then examined in reaggregated thymic organ cultures containing mixtures of monoclonal and polyclonal thymocytes. This thymocyte mixture allows for the analysis of Ag-specific events while avoiding the extreme skewing frequently seen in purely monoclonal systems. Our data indicate that thymic epithelium alone is capable of promoting self-tolerance by eliminating autoreactive CD4 single-positive thymocytes and by supporting regulatory T cell (Treg) development. We also show that both non-Treg CD4 single-positive thymocytes and Tregs are efficiently deleted by the two populations of cDCs present in the thymus, as well as to a lesser extent by MΦs. Plasmacytoid dendritic cells, B lymphocytes, and eosinophils were not able to do so. Finally, cDCs were also the most efficient THSCs at supporting Treg development in the thymus, suggesting that although they may share some characteristics required for negative selection with MΦs, they do not share those required for the support of Treg development, making cDCs a unique cell subset in the thymus.
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Affiliation(s)
- Lucia Guerri
- INSERM U932 and Centre d'Investigation Clinique, CIC-BT507, Institut Curie, Paris 75005, France.
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40
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Abstract
The mouse thymus supports T-cell development, but also contains non-T-cell lineages such as dendritic cells, macrophages, and granulocytes that are necessary for T-cell repertoire selection and apoptotic thymocyte clearance. Early thymic progenitors (ETPs) are not committed to the T-cell lineage, as demonstrated by both in vitro and in vivo assays. Whether ETPs realize non-T-cell lineage potentials in vivo is not well understood and indeed is controversial. In the present study, we investigated whether ETPs are the major precursors of any non-T-lineage cells in the thymus. We analyzed the development of these populations under experimental circumstances in which ETPs are nearly absent due to either abrogated thymic settling or inhibition of early thymic development by genetic ablation of IL-7 receptorα or Hes1. Results obtained using multiple in vivo approaches indicate that the majority of thymic granulocytes derive from ETPs. These data indicate that myelolymphoid progenitors settle the thymus and thus clarify the pathways by which stem cells give rise to downstream blood cell lineages.
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41
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Kang SJ. The bloodline of CD8α(+) dendritic cells. Mol Cells 2012; 34:219-29. [PMID: 22767247 PMCID: PMC3887845 DOI: 10.1007/s10059-012-0058-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2012] [Revised: 05/24/2012] [Accepted: 05/25/2012] [Indexed: 12/23/2022] Open
Abstract
The immune system is highly coordinated by various cell types. Dendritic cells (DCs) orchestrate immune responses at various stages and bridge innate immunity and adaptive immunity. DCs are a family of cells consisting of various subsets distinguished by surface markers, locations, and transcription factors that govern their development, differentiation, and homeostasis. The complexity of DC subset biology has hindered the understanding of the functional differences among DC subsets. The subset expressing the surface molecule CD8α is of particular interest, due to the efficiency of this DC subset in priming CD8(+) cytotoxic T cells and cross-presenting exogenous antigens to CD8(+) T cells. CD8α(+) DCs maintain tolerance to autologous antigens at steady state, but when activated secrete IL-12, polarizing T helper (Th) 1 responses. Recently, novel DC subsets were found to be present in peripheral tissues and the relationship between CD8α(+) DCs in lymphoid organs and DC subsets in peripheral tissues has been revealed. This review describes the pedigree of CD8α(+) DCs and related subsets, including a history of the discovery of DC subsets and their functional characterization.
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Affiliation(s)
- Suk-Jo Kang
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, 305-701, Korea.
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42
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Dresch C, Leverrier Y, Marvel J, Shortman K. Development of antigen cross-presentation capacity in dendritic cells. Trends Immunol 2012; 33:381-8. [PMID: 22677187 DOI: 10.1016/j.it.2012.04.009] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2012] [Revised: 04/24/2012] [Accepted: 04/24/2012] [Indexed: 02/06/2023]
Abstract
Cross-presentation by dendritic cells (DCs) of exogenous antigens on MHC class I is important for the generation of immune responses to intracellular pathogens, as well as for maintenance of self tolerance. In mice, the CD8(+) DC lineage is specialised for this role. However, DCs of this lineage are not born with cross-presentation capacity. Several studies have demonstrated that it must be induced as a later developmental step by cytokines such as granulocyte macrophage colony-stimulating factor (GM-CSF), or by microbial products such as toll-like receptor (TLR) ligands. Increased cross-presentation capacity is thus induced in peripheral CD8 lineage DCs during inflammation or infection. However, this capacity is already fully developed in steady-state thymic CD8(+) DCs, in accordance with their role in the deletion of self-reactive developing T cells.
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Affiliation(s)
- Christiane Dresch
- Institute of Virology, University of Zurich, Zurich 8057, Switzerland
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43
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Yuan C, Song G, Jiang G. The characterization and role of leukemia cell-derived dendritic cells in immunotherapy for leukemic diseases. Intractable Rare Dis Res 2012; 1:53-65. [PMID: 25343074 PMCID: PMC4204560 DOI: 10.5582/irdr.2012.v1.2.53] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2011] [Revised: 03/28/2012] [Accepted: 04/13/2012] [Indexed: 11/05/2022] Open
Abstract
Usually, an effective anti-leukemia immune response cannot be initiated effectively in patients with leukemia. This is probably related to immunosuppression due to chemotherapy, down-regulation of major histocompatibility complex (MHC) II molecules, and the lack of co-stimulatory molecules on dendritic cells (DC). In light of this problem, some methods had been used to induce leukemia cells to differentiate into mature DCs, causing them to present leukemia-associated antigens and activating naïve T cells. Furthermore, leukemia-derived DCs could be modified with tumor antigens or tumor-associated antigens to provide a new approach to anti-leukemia therapy. Numerous studies have indicated factors related to the induction and functioning of leukemia-derived DCs and the activation of cytotoxic T-lymphocytes (CTLs). These include the amount of purified DCs, cytokine profiles appropriate for inducing leukemia-derived DCs, effective methods of activating CTLs, reasonable approaches to DC vaccines, and the standardization of their clinical use. Determining these factors could lead to more effective leukemia treatment and benefit both mankind and scientific development. What follows in a review of advances in and practices of inducing leukemia-derived DCs and the feasibility of their clinical use.
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Affiliation(s)
- Changjin Yuan
- Key Laboratory for Tumor Immunology & Traditional Chinese Medicine Immunology, Key Laboratory for Rare and Uncommon Diseases of Shandong Province, Department of Hemato-Oncology, Shandong Academy of Medical Sciences, Key Laboratory for Biotech-Drugs of the Ministry of Health, Key Laboratory for Modern Medicine and Technology of Shandong Province, Ji'nan, Shandong, China
| | - Guanhua Song
- Key Laboratory for Tumor Immunology & Traditional Chinese Medicine Immunology, Key Laboratory for Rare and Uncommon Diseases of Shandong Province, Department of Hemato-Oncology, Shandong Academy of Medical Sciences, Key Laboratory for Biotech-Drugs of the Ministry of Health, Key Laboratory for Modern Medicine and Technology of Shandong Province, Ji'nan, Shandong, China
| | - Guosheng Jiang
- Key Laboratory for Tumor Immunology & Traditional Chinese Medicine Immunology, Key Laboratory for Rare and Uncommon Diseases of Shandong Province, Department of Hemato-Oncology, Shandong Academy of Medical Sciences, Key Laboratory for Biotech-Drugs of the Ministry of Health, Key Laboratory for Modern Medicine and Technology of Shandong Province, Ji'nan, Shandong, China
- Address correspondence to: Prof. Guosheng Jiang, Department of Hemato-oncology, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jingshi Road 18877, Ji'nan 250062, Shandong, China. E-mail:
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Moore AJ, Sarmiento J, Mohtashami M, Braunstein M, Zúñiga-Pflücker JC, Anderson MK. Transcriptional priming of intrathymic precursors for dendritic cell development. Development 2012; 139:373-84. [PMID: 22186727 DOI: 10.1242/dev.069344] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Specialized dendritic cells (DCs) within the thymus are crucial for the deletion of autoreactive T cells. The question of whether these cells arise from intrathymic precursors with T-cell potential has been hotly debated, and the regulatory pathways and signals that direct their development remain unclear. Here, we compared the gene expression profiles of thymic DC subsets with those of four early thymic precursor subsets: early T-cell precursors (ETPs), double-negative 1c (DN1c), double-negative 1d (DN1d) and double-negative 1e (DN1e) subsets. We found that the DN1d subset expressed Spi-B, HEBCan, Ccr7 and Ccr4, similar to thymic plasmacytoid DCs, whereas the DN1e subset expressed Id2, Ccr7 and Ccr4, similar to thymic conventional DCs. The expression of Ccr7 and Ccr4 in DN1d and DN1e cells suggested that they might be able to migrate towards the medulla (low in Dll proteins) and away from the cortex (high in Dll proteins) where early T-cell development occurs. We therefore assessed the sensitivity of developing DC precursors to Dll-Notch signaling, and found that high levels of Dll1 or Dll4 were inhibitory to DC development, whereas medium levels of Dll4 allowed DC development but not myeloid development. To evaluate directly the lineage potential of the ETP, DN1d and DN1e subsets, we injected them into nonirradiated congenic hosts intrathymically or intravenously, and found that they were all able to form medullary DCs in vivo. Therefore, DN1d and DN1e cells are transcriptionally primed to home to the thymus, migrate into DC-permissive microenvironments and develop into medullary DCs.
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Affiliation(s)
- Amanda J Moore
- Sunnybrook Research Institute, Division of Biological Sciences, Toronto, Ontario, M4N 3M5, Canada
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45
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Differential processing of self-antigens by subsets of thymic stromal cells. Curr Opin Immunol 2012; 24:99-104. [PMID: 22296716 DOI: 10.1016/j.coi.2012.01.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2011] [Revised: 01/02/2012] [Accepted: 01/09/2012] [Indexed: 12/21/2022]
Abstract
The stromal network of the thymus provides a unique environment that supports the development of mature CD4(+) and CD8(+) T cells expressing a very diverse repertoire of T cell receptors (TCR) with limited reactivity to self-antigens. Thymic cortical epithelial cells (cTECs) are specialized antigen-presenting cells (APCs) that promote the positive selection of developing thymocytes while medullary thymic epithelial cells (mTECs) and thymic dendritic cells (tDCs) induce central tolerance to self-antigens. Recent studies showed that cTECs express a unique set of proteases involved in the generation of self-peptides presented by major-histocompatibility encoded molecules (pMHC) and consequently may express a unique set of pMHC complexes. Conversely, the stromal cells of the medulla developed several mechanisms to mirror as closely as possible the constellation of self-peptides derived from peripheral tissues. Here, we discuss how these different features allow for the development of a highly diverse but poorly self-reactive repertoire of functional T cells.
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46
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González-García S, García-Peydró M, Alcain J, Toribio ML. Notch1 and IL-7 receptor signalling in early T-cell development and leukaemia. Curr Top Microbiol Immunol 2012; 360:47-73. [PMID: 22695916 DOI: 10.1007/82_2012_231] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Notch receptors are master regulators of many aspects of development and tissue renewal in metazoans. Notch1 activation is essential for T-cell specification of bone marrow-derived multipotent progenitors that seed the thymus, and for proliferation and further progression of early thymocytes along the T-cell lineage. Deregulated activation of Notch1 significantly contributes to the generation of T-cell acute lymphoblastic leukaemia (T-ALL). In addition to Notch1 signals, survival and proliferation signals provided by the IL-7 receptor (IL-7R) are also required during thymopoiesis. Our understanding of the molecular mechanisms controlling stage-specific survival and proliferation signals provided by Notch1 and IL-7R has recently been improved by the discovery that the IL-7R is a transcriptional target of Notch1. Thus, Notch1 controls T-cell development, in part by regulating the stage- and lineage-specific expression of IL-7R. The finding that induction of IL-7R expression downstream of Notch1 also occurs in T-ALL highlights the important contribution that deregulated IL-7R expression and function may have in this pathology. Confirming this notion, oncogenic IL7R gain-of-function mutations have recently been identified in childhood T-ALL. Here we discuss the fundamental role of Notch1 and IL-7R signalling pathways in physiological and pathological T-cell development in mice and men, highlighting their close molecular underpinnings.
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Affiliation(s)
- Sara González-García
- Centro de Biología Molecular, Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28049, Madrid, Spain
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Howell K, Posluszny J, He LK, Szilagyi A, Halerz J, Gamelli RL, Shankar R, Muthu K. High MafB expression following burn augments monocyte commitment and inhibits DC differentiation in hemopoietic progenitors. J Leukoc Biol 2011; 91:69-81. [PMID: 21984745 DOI: 10.1189/jlb.0711338] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
We have previously shown that perturbed bone marrow progenitor development promotes hyporesponsive monocytes following experimental burn sepsis. Clinical and experimental sepsis is associated with monocyte deactivation and depletion of mDCs. Decrease in circulating DCs is reported in burn patients who develop sepsis. In our 15% TBSA scald burn model, we demonstrate a significant reduction in the circulating MHC-II(+) population and mDCs (Gr1(neg)CD11b(+)CD11c(+)) with a corresponding decrease in bone marrow MHC-II(+) cells and mDCs for up to 14 days following burn. We explored the underlying mechanism(s) that regulate bone marrow development of monocytes and DCs following burn injury. We found a robust bone marrow response with a significant increase in multipotential HSCs (LSK) and bipotential GMPs following burn injury. GMPs from burn mice exhibit a significant reduction in GATA-1, which is essential for DC development, but express high levels of MafB and M-CSFRs, both associated with monocyte production. GMPs obtained from burn mice differentiated 1.7 times more into Mϕ and 1.6-fold less into DCs compared with sham. Monocytes and DCs expressed 50% less MHC-II in burn versus sham. Increased monocyte commitment in burn GMPs was a result of high MafB and M-CSFR expressions. Transient silencing of MafB (siRNA) in GMP-derived monocytes from burn mice partially restored DC differentiation deficits and increased GATA-1 expression. We provide evidence that high MafB following burn plays an inhibitory role in monocyte-derived DC differentiation by regulating M-CSFR and GATA-1 expressions.
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Affiliation(s)
- Kirstin Howell
- Department of Surgery, Mount Sinai Medical Center, Chicago, Illinois, USA
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Abstract
Negative selection in the thymus prevents the generation of self-reactive T cells through the deletion of thymocytes with high affinity for self-antigens. Within the thymus, self-antigens are presented by thymic epithelial cells and DCs. Both cell types can mediate negative selection, although the relative contribution of each cell type remains elusive. Similar to DCs of other lymphoid organs, thymic DCs come in different flavors. Over the past years, various lines of evidence have emerged that either favor a common origin for some thymic DCs and thymocytes or, conversely, indicate the existence of separate intrathymic T lineage and DC precursors. In this issue of the European Journal of Immunology, a study reports the identification of an intrathymic DC precursor that is likely to be unrelated to the earliest physiological T-cell progenitors. Thus this intrathymic DC precursor may constitute a "missing link" between extrathymic DC precursor-types, which are able to generate DCs in secondary lymphoid organs and intrathymic DCs, and supports the notion that intrathymic DCs and thymocytes arise from different precursors.
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Affiliation(s)
- Andreas Krueger
- Institute for Immunology, Hannover Medical School, Hannover, Germany.
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49
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Luche H, Ardouin L, Teo P, See P, Henri S, Merad M, Ginhoux F, Malissen B. The earliest intrathymic precursors of CD8α(+) thymic dendritic cells correspond to myeloid-type double-negative 1c cells. Eur J Immunol 2011; 41:2165-75. [PMID: 21630253 DOI: 10.1002/eji.201141728] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2011] [Revised: 05/20/2011] [Accepted: 05/26/2011] [Indexed: 12/16/2022]
Abstract
The dendritic cells (DCs) present in lymphoid and non-lymphoid organs are generated from progenitors with myeloid-restricted potential. However, in the thymus a major subset of DCs expressing CD8α and langerin (CD207) appears to stand apart from all other DCs in that it is thought to derive from progenitors with lymphoid potential. Using mice expressing a fluorescent reporter and a diphtheria toxin receptor under the control of the cd207 gene, we demonstrated that CD207(+) CD8α(+) thymic DCs do not share a common origin with T cells but originate from intrathymic precursors that express markers that are normally present on all (CD11c(+) and MHCII molecules) or on some (CD207, CD135, CD8α, CX3CR1) DC subsets. Those intrathymic myeloid-type precursors correspond to CD44(+) CD25(-) double-negative 1c (DN1c) cells and are continuously renewed from bone marrow-derived canonical DC precursors. In conclusion, our results demonstrate that the earliest intrathymic precursors of CD8α(+) thymic DCs correspond to myeloid-type DN1c cells and support the view that under physiological conditions myeloid-restricted progenitors generate the whole constellation of DCs present in the body including the thymus.
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Affiliation(s)
- Hervé Luche
- Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, Marseille, France
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50
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Nam HW, Ahn HJ, Yang HJ. Pro-inflammatory cytokine expression of spleen dendritic cells in mouse toxoplasmosis. THE KOREAN JOURNAL OF PARASITOLOGY 2011; 49:109-14. [PMID: 21738265 PMCID: PMC3121066 DOI: 10.3347/kjp.2011.49.2.109] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2011] [Revised: 05/03/2011] [Accepted: 05/10/2011] [Indexed: 01/17/2023]
Abstract
Dendritic cells have been known as a member of strong innate immune cells against infectious organelles. In this study, we evaluated the cytokine expression of splenic dendritic cells in chronic mouse toxoplasmosis by tissue cyst-forming Me49 strain and demonstrated the distribution of lymphoid dendritic cells by fluorescence-activated cell sorter (FACS). Pro-inflammatory cytokines, such as IL-1α, IL-1β, IL-6, and IL-10 increased rapidly at week 1 post-infection (PI) and peaked at week 3 PI. Serum IL-10 level followed the similar patterns. FACS analysis showed that the number of CD8α+/CD11c+ splenic dendritic cells increased at week 1 and peaked at week 3 PI. In conclusion, mouse splenic dendritic cells showed early and rapid cytokine changes and may have important protective roles in early phases of murine toxoplasmosis.
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Affiliation(s)
- Ho-Woo Nam
- Department of Parasitology, College of Medicine, Catholic University of Korea, Seoul 137-701, Korea
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