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1
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The promise and challenges of immune agonist antibody development in cancer. Nat Rev Drug Discov 2018; 17:509-527. [PMID: 29904196 DOI: 10.1038/nrd.2018.75] [Citation(s) in RCA: 277] [Impact Index Per Article: 39.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Immune cell functions are regulated by co-inhibitory and co-stimulatory receptors. The first two generations of cancer immunotherapy agents consist primarily of antagonist antibodies that block negative immune checkpoints, such as programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte protein 4 (CTLA4). Looking ahead, there is substantial promise in targeting co-stimulatory receptors with agonist antibodies, and a growing number of these agents are making their way through various stages of development. This Review discusses the key considerations and potential pitfalls of immune agonist antibody design and development, their differentiating features from antagonist antibodies and the landscape of agonist antibodies in clinical development for cancer treatment.
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2
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Rashin AA, Jernigan RL. Clusters of Structurally Similar MHC I HLA-A2 Molecules, Found with a New Method, Suggest Mechanisms of T-Cell Receptor Avidity. Biochemistry 2016; 55:167-85. [PMID: 26600404 DOI: 10.1021/acs.biochem.5b01077] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Only α1 and α2 domains of the α-chain of the major histocompatibility complex (MHC) directly bind peptide antigens (Ag-s) and the T-cell receptor (TCR). Significant plasticity was found in the TCR but only minor in (α1 + α2). The α3-domain position variation was noted only in connection to its binding the coreceptor CD8. We apply our methods for identifying functional conformational changes in proteins to a systematic study of similarities between 43 X-ray structures of the entire α chains of MHC-I HLA-A2. Out of 903 different αHLA-A2 pairs 203 show similarities within the earlier determined uncertainty threshold and unexpectedly form three similarity clusters (SCs) with all/most structures in a cluster similar within the uncertainty threshold. Pairs from different SCs always differ above the threshold, mainly due to variations in the α3 position/structure. All structures in SC3 cannot bind the CD8 coreceptor. Strong hydrogen bonds between (α1 + α2) and α3 differ between SC1 and SC2 but are nearly invariant within each SC. Small conformational changes in the (α1 + α2), caused by Ag-s differences, act as an α3 "allosteric switch" between SC2 and SC1. Binding of CD8 to SC2-HLA-A2 (Tax-type Ag-s) changes it to SC1-HLA-A2 (HuD-type Ag-s). HuD binding to HLA-A2 is much less stable than Tax binding. CD8-liganded HLA-A2 preference for binding HuD suggests that CD8-HLA-A2 may present a weakly binding peptide for TCR recognition, supporting the hypothesis that CD8 increases TCR avidity to weak Ag-s. Other HLA-A2 functions may involve α3. TCR-A6-liganded-Tax-type-HLA-A2s form two small clusters, similar to either A6-liganded-HuD or A6-liganded-native-Tax HLA-A2s.
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Affiliation(s)
- Alexander A Rashin
- BioChemComp Inc , 543 Sagamore Avenue, Teaneck, New Jersey 07666, United States
- LH Baker Center for Bioinformatics and Department of Biochemistry, Biophysics and Molecular Biology, 112 Office and Lab Building, Iowa State University , Ames, Iowa 50011-3020, United States
| | - Robert L Jernigan
- LH Baker Center for Bioinformatics and Department of Biochemistry, Biophysics and Molecular Biology, 112 Office and Lab Building, Iowa State University , Ames, Iowa 50011-3020, United States
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3
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Thurley K, Gerecht D, Friedmann E, Höfer T. Three-Dimensional Gradients of Cytokine Signaling between T Cells. PLoS Comput Biol 2015; 11:e1004206. [PMID: 25923703 PMCID: PMC4414419 DOI: 10.1371/journal.pcbi.1004206] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 02/17/2015] [Indexed: 11/20/2022] Open
Abstract
Immune responses are regulated by diffusible mediators, the cytokines, which act at sub-nanomolar concentrations. The spatial range of cytokine communication is a crucial, yet poorly understood, functional property. Both containment of cytokine action in narrow junctions between immune cells (immunological synapses) and global signaling throughout entire lymph nodes have been proposed, but the conditions under which they might occur are not clear. Here we analyze spatially three-dimensional reaction-diffusion models for the dynamics of cytokine signaling at two successive scales: in immunological synapses and in dense multicellular environments. For realistic parameter values, we observe local spatial gradients, with the cytokine concentration around secreting cells decaying sharply across only a few cell diameters. Focusing on the well-characterized T-cell cytokine interleukin-2, we show how cytokine secretion and competitive uptake determine this signaling range. Uptake is shaped locally by the geometry of the immunological synapse. However, even for narrow synapses, which favor intrasynaptic cytokine consumption, escape fluxes into the extrasynaptic space are expected to be substantial (≥20% of secretion). Hence paracrine signaling will generally extend beyond the synapse but can be limited to cellular microenvironments through uptake by target cells or strong competitors, such as regulatory T cells. By contrast, long-range cytokine signaling requires a high density of cytokine producers or weak consumption (e.g., by sparsely distributed target cells). Thus in a physiological setting, cytokine gradients between cells, and not bulk-phase concentrations, are crucial for cell-to-cell communication, emphasizing the need for spatially resolved data on cytokine signaling. The adaptive immune system fights pathogens through the activation of immune cell clones that specifically recognize a particular pathogen. Tight contacts, so-called immunological synapses, of immune cells with cells that present ‘digested’ pathogen molecules are pivotal for ensuring specificity. The discovery that immune responses are regulated by small diffusible proteins – the cytokines – has been surprising because cytokine diffusion to ‘bystander’ cells might compromise specificity. It has therefore been argued that cytokines are trapped in immunological synapses, whereas other authors have found that cytokines act on a larger scale through entire lymph nodes. Measurements of cytokine concentrations with fine spatial resolution have not been achieved. Here, we study the spatio-temporal dynamics of cytokines through mathematical analysis and three-dimensional numerical simulation and identify key parameters that control signaling range. We predict that even tight immunological synapses leak a substantial portion of the secreted cytokines. Nevertheless, rapid cellular uptake will render cytokine signals short-range and thus incidental activation of bystander cells can be limited. Long-range signals will only occur with multiple secreting cells or/and slow consumption by sparse target cells. Thus our study identifies key determinants of the spatial range of cytokine communication in realistic multicellular geometries.
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Affiliation(s)
- Kevin Thurley
- Division of Theoretical Systems Biology, German Cancer Research Center, Heidelberg, Germany
- Institute for Theoretical Biology, Charité-Universitätsmedizin, Berlin, Germany
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, United States of America
- * E-mail: (KT); (DG); (EF); (TH)
| | - Daniel Gerecht
- Institute for Applied Mathematics, University of Heidelberg, Heidelberg, Germany
- * E-mail: (KT); (DG); (EF); (TH)
| | - Elfriede Friedmann
- Institute for Applied Mathematics, University of Heidelberg, Heidelberg, Germany
- * E-mail: (KT); (DG); (EF); (TH)
| | - Thomas Höfer
- Division of Theoretical Systems Biology, German Cancer Research Center, Heidelberg, Germany
- Bioquant Center, University of Heidelberg, Heidelberg, Germany
- * E-mail: (KT); (DG); (EF); (TH)
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4
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Gleeson PA. The role of endosomes in innate and adaptive immunity. Semin Cell Dev Biol 2014; 31:64-72. [PMID: 24631355 DOI: 10.1016/j.semcdb.2014.03.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Revised: 02/28/2014] [Accepted: 03/01/2014] [Indexed: 12/16/2022]
Abstract
The regulation of the immune system is critical for the generation of effective immune responses to a range of pathogens, as well as for protection against unwanted responses. The regulation of many immune response pathways are directly dependent on the organisation and activities of intracellular endosomal compartments associated with cargo sorting, membrane trafficking and signalling. Over the last 5-10 years, the appreciation of the important contribution of the endosomal system has expanded dramatically to include antigen presentation of MHC class I, MHC class II and CD1 molecules, as well as the regulation of antigen receptor signalling and pattern recognition receptor signalling of the innate immune system. This review summarises some of the very diverse and key roles played by endosomes in generating effective innate and adaptive immune responses.
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Affiliation(s)
- Paul A Gleeson
- The Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia.
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5
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Genetic and Epigenetic Regulation of CCR5 Transcription. BIOLOGY 2012; 1:869-79. [PMID: 24832521 PMCID: PMC4009821 DOI: 10.3390/biology1030869] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/07/2012] [Revised: 11/27/2012] [Accepted: 12/03/2012] [Indexed: 12/21/2022]
Abstract
The chemokine receptor CCR5 regulates trafficking of immune cells of the lymphoid and the myeloid lineage (such as monocytes, macrophages and immature dendritic cells) and microglia. Because of this, there is an increasing recognition of the important role of CCR5 in the pathology of (neuro-) inflammatory diseases such as atherosclerosis and multiple sclerosis. Expression of CCR5 is under the control of a complexly organized promoter region upstream of the gene. The transcription factor cAMP-responsive element binding protein 1 (CREB-1) transactivates the CCR5 P1 promoter. The cell-specific expression of CCR5 however is realized by using various epigenetic marks providing a multivalent chromatin state particularly in monocytes. Here we discuss the transcriptional regulation of CCR5 with a focus on the epigenetic peculiarities of CCR5 transcription.
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6
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Wierda RJ, Kuipers HF, van Eggermond MCJA, Benard A, van Leeuwen JC, Carluccio S, Geutskens SB, Jukema JW, Marquez VE, Quax PHA, van den Elsen PJ. Epigenetic control of CCR5 transcript levels in immune cells and modulation by small molecules inhibitors. J Cell Mol Med 2012; 16:1866-77. [PMID: 22050776 PMCID: PMC3309068 DOI: 10.1111/j.1582-4934.2011.01482.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Previously, we have shown that CCR5 transcription is regulated by CREB-1. However, the ubiquitous pattern of CREB-1 expression suggests the involvement of an additional level of transcriptional control in the cell type–specific expression of CCR5. In this study, we show that epigenetic changes (i.e. DNA methylation and histone modifications) within the context of the CCR5 P1 promoter region correlate with transcript levels of CCR5 in healthy and in malignant CD4+ T lymphocytes as well as in CD14+ monocytes. In normal naïve T cells and CD14+ monocytes the CCR5 P1 promoter resembles a bivalent chromatin state, with both repressive and permissive histone methylation and acetylation marks. The CCR5-expressing CD14+ monocytes however show much higher levels of acetylated histone H3 (AcH3) compared to the non–CCR5-expressing naïve T cells. Combined with a highly methylated promoter in CD14+ monocytes, this indicates a dominant role for AcH3 in CCR5 transcription. We also show that pharmacological interference in the epigenetic repressive mechanisms that account for the lack of CCR5 transcription in T leukaemic cell lines results in an increase in CREB-1 association with CCR5 P1 chromatin. Furthermore, RNA polymerase II was also recruited into CCR5 P1 chromatin resulting in CCR5 re-expression. Together, these data indicate that epigenetic modifications of DNA, and of histones, contribute to the control of CCR5 transcription in immune effector cells.
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Affiliation(s)
- Rutger J Wierda
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
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7
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Pre-existing clusters of the adaptor Lat do not participate in early T cell signaling events. Nat Immunol 2011; 12:655-62. [PMID: 21642986 DOI: 10.1038/ni.2049] [Citation(s) in RCA: 248] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2011] [Accepted: 05/05/2011] [Indexed: 01/21/2023]
Abstract
Engaged T cell antigen receptors (TCRs) initiate signaling through the adaptor protein Lat. In quiescent T cells, Lat is segregated into clusters on the cell surface, which raises the question of how TCR triggering initiates signaling. Using super-resolution fluorescence microscopy, we found that pre-existing Lat domains were neither phosphorylated nor laterally transported to TCR activation sites, which suggested that these clusters do not participate in TCR signaling. Instead, TCR activation resulted in the recruitment and phosphorylation of Lat from subsynaptic vesicles. Studies of Lat mutants confirmed that recruitment preceded and was essential for phosphorylation and that both processes were independent of surface clustering of Lat. Our data suggest that TCR ligation preconditions the membrane for vesicle recruitment and bulk activation of the Lat signaling network.
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8
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Manz BN, Groves JT. Spatial organization and signal transduction at intercellular junctions. Nat Rev Mol Cell Biol 2010; 11:342-52. [PMID: 20354536 PMCID: PMC3693730 DOI: 10.1038/nrm2883] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The coordinated organization of cell membrane receptors into diverse micrometre-scale spatial patterns is emerging as an important theme of intercellular signalling, as exemplified by immunological synapses. Key characteristics of these patterns are that they transcend direct protein-protein interactions, emerge transiently and modulate signal transduction. Such cooperativity over multiple length scales presents new and intriguing challenges for the study and ultimate understanding of cellular signalling. As a result, new experimental strategies have emerged to manipulate the spatial organization of molecules inside living cells. The resulting spatial mutations yield insights into the interweaving of the spatial, mechanical and chemical aspects of intercellular signalling.
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Affiliation(s)
- Boryana N. Manz
- Howard Hughes Medical Institute, Department of Chemistry, University of California, Berkeley California 94720, USA
- Biophysics Graduate Group, Lawrence Berkeley National Lab, Berkeley, California 94720, USA
| | - Jay T. Groves
- Howard Hughes Medical Institute, Department of Chemistry, University of California, Berkeley California 94720, USA
- Biophysics Graduate Group, Lawrence Berkeley National Lab, Berkeley, California 94720, USA
- Physical Biosciences and Materials Sciences Divisions, Lawrence Berkeley National Lab, Berkeley, California 94720, USA
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Rodríguez-Fernández JL, Riol-Blanco L, Delgado-Martín C. What is the function of the dendritic cell side of the immunological synapse? Sci Signal 2010; 3:re2. [PMID: 20086241 DOI: 10.1126/scisignal.3105re2] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The adaptive immune response requires the formation of a specialized interface called the immunological synapse (IS), which is formed between a mature dendritic cell (DC) and a CD4(+) T cell in the lymph node. The IS involves organized motifs formed by cell-surface and cytoplasmic molecules at both the DC side (IS-DC) and the T cell side (IS-T) of the IS. Most studies of the functions of the IS have focused on the IS-T; however, to understand the function(s) of the entire IS, it is also necessary to gain insight into the role(s) of the IS-DC. Unlike T cells, which upon their activation leave the lymph node and return to the circulation, DCs largely become apoptotic and die in the node region. This latter observation and the known stability of the IS, which may last for hours, is consistent with the hypothesis that one of the functions of the IS-DC could be the temporal inhibition of the apoptosis of DCs, which would enable the activation of clonal T cells in the lymph nodes. Here, we discuss experimental data supporting the latter hypothesis, as well as the concept that the IS-DC is a signaling region that contributes to the functions of the IS.
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Affiliation(s)
- José Luis Rodríguez-Fernández
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, C/ Ramiro de Maeztu, 9, 28040 Madrid, Spain.
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10
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Dendritic cell microvilli: a novel membrane structure associated with the multifocal synapse and T-cell clustering. Blood 2008; 112:5037-45. [PMID: 18805966 DOI: 10.1182/blood-2008-04-149526] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Polarizing effects of productive dendritic cell (DC)-T-cell interactions on DC cytoskeleton have been known in some detail, but the effects on DC membrane have been studied to a lesser extent. We found that T-cell incubation led to DC elongation and segregation of characteristic DC veils to the broader pole of the cell. On the opposite DC pole, we observed a novel membrane feature in the form of bundled microvilli. Each villus was approximately 100 nm in diameter and 600 to 1200 nm long. Microvilli exhibited high density of antigen-presenting molecules and costimulatory molecules and provided the physical basis for the multifocal immune synapse we observed during human DC and T-cell interactions. T cells preferentially bound to this site in clusters often contained both CD4(+) and CD8(+) T cells.
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11
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Hu Q, Pan Z, Deen S, Meng S, Zhang X, Zhang X, Jiao XA. New alleles of chicken CD8 alpha and CD3d found in Chinese native and western breeds. Vet Immunol Immunopathol 2007; 120:223-33. [PMID: 17904644 DOI: 10.1016/j.vetimm.2007.08.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2007] [Revised: 08/01/2007] [Accepted: 08/13/2007] [Indexed: 02/02/2023]
Abstract
Chinese native chicken breeds provide useful resources for the study of genetic diversity. In this study, the alleles of CD8 alpha and CD3d cDNA from Chinese native and introduced western breeds of chicken were analyzed at the sequence level. Six alleles were found, due to 13 amino acid replacements in the extracellular domain of the CD8 alpha sequence. There were four alleles detected in the Chinese strains, and alleles 5 and 6 were identified for the first time. Allele 6 was shared by Langshan, Beijing Fatty and Recessive White Feather chickens. Allele 2, found in the Bigbone strain, was the same as that found in the Leghorn strain H.B15.H7, and allele 3 in the Xianju breed was also the same as in the Leghorn strain H.B15.H12. Two Leghorn lines (RPL line 7 and AY519197) and the Camellia possessed an allele (alleles 1, 4 and 5), respectively, that was not found in the other lines. Nine out of 13 amino acid replacements were situated in the putative major histocompatibility complex (MHC) class I binding CDR1 (positions 30, 33 and 34), CDR2 (positions 58, 62, 63 and 65) and CDR3 (positions 90 and 106). Except for the Xianju breed, the CD8 alpha cDNA of Chinese native chicken breeds shared high homology. Two alleles were found in CD3d. Three additional nucleotides were found at positions 64, 65 and 66 in the newly discovered allele 2. This led to a difference of four amino acids (at residues 22, 23, 24 and 25) in the extracellular domain of CD3d cDNA from the Gushi, Recessive White Feather and ISA chickens compared with these of the White Leghorn and T11.15 (NM_205512). Five hybridoma clones (1C9, 1H5, 4B11, 6G5 and 13C5) against chicken CD8 alpha were generated by DNA immunization. Two monoclonal antibodies (mAbs), 6G5 and 4B11, showed reactivity to the splenocytes from five Chinese native chicken breeds, the Recessive White Feather chicken and the Leghorn (AY519197), while mAbs 1C9, 1H5 and 13C5 showed no reaction with these breeds.
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Affiliation(s)
- Qinghai Hu
- College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou, Jiangsu 225009, China
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12
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He T, Zong S, Wu X, Wei Y, Xiang J. CD4+ T cell acquisition of the bystander pMHC I colocalizing in the same immunological synapse comprising pMHC II and costimulatory CD40, CD54, CD80, OX40L, and 41BBL. Biochem Biophys Res Commun 2007; 362:822-8. [PMID: 17803957 DOI: 10.1016/j.bbrc.2007.08.072] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2007] [Accepted: 08/07/2007] [Indexed: 10/22/2022]
Abstract
We previously showed that CD4+ T cells acquired peptide/major histocompatibility complex (pMHC) I and costimulatory molecules by dendritic cell (DC) activation. However, the molecular mechanism for pMHC I acquisition is unclear. In this study, by using a panel of engineered DC2.4 cells or incubation of these cells with Con A-stimulated CD4+ T cells, we conducted capping and synapse formation assay and examined them by confocal fluorescence microscopy. We demonstrated that (i) CD54 and CD80 colocalized with pMHC I/II in the same lipid rafts, whereas CD40, OX40L, and 41BBL localized in the lipid rafts but separately from pMHC I/II, and (ii) MHC I/II colocalized with the costimulatory molecules in the same synapse formed between a DC and a CD4+ T cell, leading to expression of the acquired bystander pMHC I on CD4+ T cells via internalization/recycling pathway. These results provide some useful information in composition and dynamics of immunological synapses.
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Affiliation(s)
- Tianpei He
- Research Unit, Saskatchewan Cancer Agency, Department of Oncology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 4H4
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13
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Pawlowski NN, Struck D, Grollich K, Kuhl AA, Zeitz M, Liesenfeld O, Hoffmann JC. CD2 deficiency partially prevents small bowel inflammation and improves parasite control in murine Toxoplasma gondii infection. World J Gastroenterol 2007; 13:4207-13. [PMID: 17696249 PMCID: PMC4250619 DOI: 10.3748/wjg.v13.i31.4207] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether bowel inflammation and/or parasite control is altered in the absence of the T cell adhesion molecule CD2.
METHODS: Wildtype (WT) and CD2 deficient (CD2-/-) mice were infected with 100 cysts of Toxoplasma gondii (T. gondii) (ME49) by gavage. On d 7 after infection mice were killed. Necrosis and the number of parasites/cm ileum were determined. Cytokine levels of stimulated cells as well as sera were evaluated. Secondly, survival of WT vs CD2-/- mice was analysed using Kaplan-Meier analysis.
RESULTS: CD2-/- mice survived longer than WT mice (mean: 23.5 vs 7.1 d, P = 0.001). Further, CD2-/- mice showed less weight loss and less ileal inflammation than WT mice at d 7 post infection. In addition, the number of parasites in the ileum was significantly lower in CD2-/- mice than in WT mice (88 ± 12 vs 349 ± 58 cm, P < 0.01). This was paralleled by lower production of IFN-γ and IL-6 from TLA-stimulated mLN cells and increased IFN-γ production by splenocytes.
CONCLUSION: CD2 deficient mice are more resistant to T. gondii infection than WT mice. In contrast to most current immunosuppressive or biological therapies CD2 deficiency reduces intestinal inflammation and at the same time helps to control infection.
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Affiliation(s)
- Nina-N Pawlowski
- Medizinische Klinik I, St. Charité-Universitätsmedizin Berlin, Berlin, Germany
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14
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Kuipers HF, van den Elsen PJ. Immunomodulation by statins: Inhibition of cholesterol vs. isoprenoid biosynthesis. Biomed Pharmacother 2007; 61:400-7. [PMID: 17643927 DOI: 10.1016/j.biopha.2007.06.005] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2007] [Accepted: 06/11/2007] [Indexed: 01/30/2023] Open
Abstract
Due to their ability to inhibit the synthesis of cholesterol, statins are widely used in medical practice and are the principal therapy for hypercholesterolemia. In addition, various findings suggest that statins also exert anti-inflammatory properties and may so play a role in modulating the immune system. Because of these properties, statins could provide a potential treatment for various chronic inflammatory diseases, including neuroinflammatory disorders such as multiple sclerosis. Here, we will review the effect of statins on the expression and function of a variety of immune relevant molecules and the underlying mechanisms that contribute to the immunomodulatory properties of statins. In this discussion we will also evaluate the effects of statins on central nervous system cells to emphasize the potential of these agents in the treatment of neuroinflammatory disorders.
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Affiliation(s)
- Hedwich F Kuipers
- Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
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15
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Chirifu M, Hayashi C, Nakamura T, Toma S, Shuto T, Kai H, Yamagata Y, Davis SJ, Ikemizu S. Crystal structure of the IL-15-IL-15Ralpha complex, a cytokine-receptor unit presented in trans. Nat Immunol 2007; 8:1001-7. [PMID: 17643103 DOI: 10.1038/ni1492] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2007] [Accepted: 06/20/2007] [Indexed: 12/11/2022]
Abstract
Interleukin 15 (IL-15) and IL-2, which promote the survival of memory CD8(+) T cells and regulatory T cells, respectively, bind receptor complexes that share beta- and gamma-signaling subunits. Receptor specificity is provided by unique, nonsignaling alpha-subunits. Whereas IL-2 receptor-alpha (IL-2Ralpha) is expressed together in cis with the beta- and gamma-subunits on T cells and B cells, IL-15Ralpha is expressed in trans on antigen-presenting cells. Here we present a 1.85-A crystal structure of the human IL-15-IL-15Ralpha complex. The structure provides insight into the molecular basis of the specificity of cytokine recognition and emphasizes the importance of water in generating this very high-affinity complex. Despite very low IL-15-IL-2 sequence homology and distinct receptor architecture, the topologies of the IL-15-IL-15Ralpha and IL-2-IL-2Ralpha complexes are very similar. Our data raise the possibility that IL-2, like IL-15, might be capable of being presented in trans in the context of its unique receptor alpha-chain.
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Affiliation(s)
- Mami Chirifu
- Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan
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16
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Hao S, Yuan J, Xiang J. Nonspecific CD4(+) T cells with uptake of antigen-specific dendritic cell-released exosomes stimulate antigen-specific CD8(+) CTL responses and long-term T cell memory. J Leukoc Biol 2007; 82:829-38. [PMID: 17626150 DOI: 10.1189/jlb.0407249] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Dendritic cell (DC) and DC-derived exosomes (EXO) have been used extensively for tumor vaccination. However, its therapeutic efficiency is limited to only production of prophylactic immunity against tumors. T cells can uptake DC-released EXO. However, the functional effect of transferred exosomal molecules on T cells is unclear. In this study, we demonstrated that OVA protein-pulsed DC-derived EXO (EXO(OVA)) can be taken up by Con A-stimulated, nonspecific CD4(+) T cells derived from wild-type C57BL/6 mice. The active EXO-uptaken CD4(+) T cells (aT(EXO)), expressing acquired exosomal MHC I/OVA I peptide (pMHC I) complexes and costimulatory CD40 and CD80 molecules, can act as APCs capable of stimulating OVA-specific CD8(+) T cell proliferation in vitro and in vivo and inducing efficient CD4(+) Th cell-independent CD8(+) CTL responses in vivo. The EXO(OVA)-uptaken CD4(+) aT(EXO) cell vaccine induces much more efficient CD8(+) T cell responses and immunity against challenge of OVA-transfected BL6-10 melanoma cells expressing OVA in wild-type C57BL/6 mice than EXO(OVA). The in vivo stimulatory effect of the CD4(+) aT(EXO) cell to CD8(+) T cell responses is mediated and targeted by its CD40 ligand signaling/acquired exosomal CD80 and pMHC I complexes, respectively. In addition, CD4(+) aT(EXO) vaccine stimulates a long-term, OVA-specific CD8(+) T cell memory. Therefore, the EXO(OVA)-uptaken CD4(+) T cells may represent a new, effective, EXO-based vaccine strategy in induction of immune responses against tumors and other infectious diseases.
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Affiliation(s)
- Siguo Hao
- Research Unit, Division of Health Research, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, Canada
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17
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Choudhuri K, van der Merwe PA. Molecular mechanisms involved in T cell receptor triggering. Semin Immunol 2007; 19:255-61. [PMID: 17560121 DOI: 10.1016/j.smim.2007.04.005] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2007] [Accepted: 04/14/2007] [Indexed: 12/19/2022]
Abstract
Despite intensive investigation we still do not understand how the T cell antigen receptor (TCR) tranduces signals across the plasma membrane, a process referred to as TCR triggering. Three basic mechanisms have been proposed, involving aggregation, conformational change, or segregation of the TCR upon binding pMHC ligand. Given the low density of pMHC ligand it remains doubtful that TCR aggregation initiates triggering, although it is likely to enhance subsequent signalling. Structural studies to date have not provided definitive evidence for or against a conformational change mechanism, but they have ruled out certain types of conformational change. Size-induced segregation of the bound TCR from inhibitory membrane tyrosine phosphatases seems to be required, but is probably not the only mechanism. Current evidence suggests that TCR triggering is initiated by a combination of segregation and conformational change, with subsequent aggregation contributing to amplification of the signal.
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Affiliation(s)
- Kaushik Choudhuri
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom
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18
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Wabnitz GH, Köcher T, Lohneis P, Stober C, Konstandin MH, Funk B, Sester U, Wilm M, Klemke M, Samstag Y. Costimulation induced phosphorylation of L-plastin facilitates surface transport of the T cell activation molecules CD69 and CD25. Eur J Immunol 2007; 37:649-62. [PMID: 17294403 DOI: 10.1002/eji.200636320] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Rearrangements in the actin cytoskeleton play a pivotal role for costimulation-induced formation of the immunological synapse and T cell activation. Yet, little is known about the actin-binding proteins that link costimulation to rearrangements in the actin cytoskeleton. Here we demonstrate that phosphorylation of the actin bundling protein L-plastin in response to costimulation through TCR/CD3 plus CD2 or CD28, respectively, is important for the activation of human peripheral blood T lymphocytes (PBT). Mass spectrometry and site-directed mutagenesis revealed that Ser5 represents the only phospho-acceptor site of L-plastin in PBT. Wild-type L-plastin (wt-LPL) and a non-phosphorylatable 5A-L-plastin (5A-LPL) equally relocalized to the immunological synapse between PBT and APC. Yet importantly, cells expressing 5A-LPL showed a significantly lower expression of the T cell activation molecules CD25 and CD69 on the cell surface than cells expressing wt-LPL. This effect is due to a failure in the transport of CD25 and CD69 to the cell surface since the total amount of these proteins within the cells remained unchanged. In conclusion, phosphorylation of the actin bundling protein L-plastin represents a so-far-unknown mechanism by which costimulation controls the transport of activation receptors to the T cell surface.
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Affiliation(s)
- Guido H Wabnitz
- Institute for Immunology, Ruprecht-Karls-University, Heidelberg, Germany
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19
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Abstract
Interactions between discrete and independent cells, immune or otherwise, present a variety of potential problems. How do you make sure the cells can communicate effectively? How do you preclude neighboring cells from "listening in on a conversation" that may be meant only for one set of "ears"? How can you sharpen the hearing of those ears so they will be capable of detecting small signals but not get distracted by random noise in the system? How can you selectively enhance the sense of hearing in times of great need or urgency and then diminish the "gain" of the system when it is not immediately required? How can you assure that the call will be terminated at the end of the conversation? Passage of communication molecules and/or interaction of cell surface markers require close and stable apposition of the cell delivering the message with the receiving cell. In the nervous system, these problems were successfully addressed in the nerve-nerve or nerve-myocyte (neuromuscular junction) synapses. Not surprisingly, given the parsimony of nature, the immune system uses some of the same design features, even some of the same molecules, to achieve an effective communication strategy. The term "immunologic synapse" was coined only 2 decades ago, but the structure it describes has become a very hot topic in immunology and cell biology. The immunologic synapse allows the activation of a unique T cell, with an antigen receptor recognizing its antigen in the grasp of the antigen-presenting cell's (APC's) major histocompatibility complex (MHC). A better understanding of this transient immune cell-cell interactive structure allows one to weave the functions of T cell antigen receptors, lipid rafts, adaptor molecules, and nuclear signaling molecules together into one cohesive, flowing communication supersystem. Appreciation of the intricacies of the synapse also identifies targets that one day may be used to interfere with antigen-specific immune responses, eg, autoimmunity.
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Affiliation(s)
- Leonard H Sigal
- Pharmaceutical Research Institute/Bristol-Myers Squibb, J.3100, PO Box 4000, Princeton, NJ 08543, USA.
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20
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Russell S, Oliaro J. Compartmentalization in T‐cell signalling: Membrane microdomains and polarity orchestrate signalling and morphology. Immunol Cell Biol 2006; 84:107-13. [PMID: 16405658 DOI: 10.1111/j.1440-1711.2005.01415.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Lymphocyte function is regulated by complex signalling responses to diverse extracellular inputs, and a cell will often receive multiple, conflicting signals at one time. The mechanisms by which a lymphocyte integrates these signals into a single cellular response are not well understood. An important factor in the integration of signals likely involves the regulation of access of signalling molecules to cell surface receptors and of receptor signals to morphological determinants within the cell. Recent studies have led to important advances in our understanding of both the mechanisms by which signals are compartmentalized in T cells and the physiological role played by such compartmentalization. We review progress in the field, with a particular focus on membrane microdomains or lipid rafts and on cell polarity.
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Affiliation(s)
- Sarah Russell
- Immune Signalling Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
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21
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Groves JT. Molekulare Organisation und Signaltransduktion an Kontaktstellen zwischen Membranen. Angew Chem Int Ed Engl 2005. [DOI: 10.1002/ange.200461014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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22
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Groves JT. Molecular Organization and Signal Transduction at Intermembrane Junctions. Angew Chem Int Ed Engl 2005; 44:3524-38. [PMID: 15844101 DOI: 10.1002/anie.200461014] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Surfaces create an environment in which multiple forces conspire together to yield a wealth of complex chemical processes. This is especially true of cell membranes, whose fluidity and flexibility enables responsive feedback with surface chemical interactions in ways not generally seen with inorganic materials. Spatial pattern formation of cell-surface proteins at intermembrane junctions provides many beautiful examples of these phenomena, and is also emerging as a functional aspect of intercellular signaling. Correspondingly, the study of interactions of cell-membrane surfaces is attracting significant attention from cell biologists and physical chemists alike. This convergence is fueled be recent, exquisite observations of protein pattern formation events within living immunological synapses along with parallel advances in membrane reconstitution, manipulation, and imaging technologies.
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Affiliation(s)
- Jay T Groves
- Department of Chemistry, University of California Berkeley, USA.
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23
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Kuipers HF, Biesta PJ, Groothuis TA, Neefjes JJ, Mommaas AM, van den Elsen PJ. Statins Affect Cell-Surface Expression of Major Histocompatibility Complex Class II Molecules by Disrupting Cholesterol-Containing Microdomains. Hum Immunol 2005; 66:653-65. [PMID: 15993711 DOI: 10.1016/j.humimm.2005.04.004] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2005] [Revised: 04/07/2005] [Accepted: 04/11/2005] [Indexed: 11/18/2022]
Abstract
Statins, the main therapy for hypercholesterolemia, are currently considered as possible immunomodulatory agents. Statins inhibit the production of proinflammatory cytokines and reduce the expression of several immunoregulatory molecules, including major histocompatibility complex class II (MHC-II) molecules. In this study, we investigated the mechanism by which simvastatin reduces the membrane expression of MHC-II molecules on several human cell types. We demonstrate that the reduction of MHC-II membrane expression by simvastatin correlates with disruption of cholesterol-containing microdomains, which transport and concentrate MHC-II molecules to the cell surface. In addition, we demonstrate that statins reduce cell-surface expression of other immunoregulatory molecules, which include MHC-I, CD3, CD4, CD8, CD28, CD40, CD80, CD86, and CD54. Our observations indicate that the downregulation of MHC-II at the cell surface contributes to the immunomodulatory properties of statins and is achieved through disruption of cholesterol-containing microdomains, which are involved in their intracellular transport.
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Affiliation(s)
- Hedwich F Kuipers
- Division of Molecular Biology, Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
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24
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Coombs D, Goldstein B. Effects of the geometry of the immunological synapse on the delivery of effector molecules. Biophys J 2005; 87:2215-20. [PMID: 15454424 PMCID: PMC1304647 DOI: 10.1529/biophysj.104.045674] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Recent experiments focusing on the function of the immunological synapse formed between a T cell and an antigen-presenting cell raise many questions about its purpose. We examine the proposal that the close apposition of the cell membranes in the central region of the synapse acts to focus T-cell secretions on the target cell, thus reducing the effect on nearby cells. We show that the efficiency of targeted T-cell responses to closely apposed cells is only weakly dependent on the distance between the cells. We also calculate effective (diffusion-limited) rates of binding and unbinding for molecules secreted within the synapse. We apply our model to the stimulation of B cells by secreted interleukin-4 (IL-4), and find that very few molecules of IL-4 need be released to essentially saturate the IL-4 receptors on the B-cell surface.
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Affiliation(s)
- Daniel Coombs
- Department of Mathematics, University of British Columbia, Vancouver, British Columbia V6T 1Z2, Canada.
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25
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Abstract
The ZAP-70 tyrosine kinase has been described more than ten years ago. Its key role in thymocytes development and mature T lymphocytes activation has been illustrated by the characterization of several human immunodeficiencies presenting with mutations in the zap-70 gene resulting in the absence of ZAP-70 expression. More recently, it has been shown that deregulation of ZAP-70 activity can induce autoimmune diseases. Finally, ZAP-70 expression has been shown in some B chronic lymphocytic leukaemia and correlated with bad prognosis of the disease. The diversity of pathologies associated with deregulation of ZAP-70 demonstrates its key role in immune responses. Research aiming at deciphering the different signalling pathways regulated by ZAP-70 will not only shed some lights on these pathologies, but will also help finding new pharmacological tools, targeting ZAP-70, designed to induce immunosuppression or tolerance.
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Affiliation(s)
- Claire Hivroz
- Inserm U.365, Institut Curie, Section Recherche, 26, rue d'Ulm, 75248 Paris Cedex 05, France.
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26
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Koneru M, Schaer D, Monu N, Ayala A, Frey AB. Defective Proximal TCR Signaling Inhibits CD8+ Tumor-Infiltrating Lymphocyte Lytic Function. THE JOURNAL OF IMMUNOLOGY 2005; 174:1830-40. [PMID: 15699109 DOI: 10.4049/jimmunol.174.4.1830] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
CD8+ tumor-infiltrating lymphocytes (TIL) are severely deficient in cytolysis, a defect that may permit tumor escape from immune-mediated destruction. Because lytic function is dependent upon TCR signaling, we have tested the hypothesis that primary TIL have defective signaling by analysis of the localization and activation status of TIL proteins important in TCR-mediated signaling. Upon conjugate formation with cognate target cells in vitro, TIL do not recruit granzyme B+ granules, the microtubule-organizing center, F-actin, Wiskott-Aldrich syndrome protein, nor proline rich tyrosine kinase-2 to the target cell contact site. In addition, TIL do not flux calcium nor demonstrate proximal tyrosine kinase activity, deficiencies likely to underlie failure to fully activate the lytic machinery. Confocal microscopy and fluorescence resonance energy transfer analyses demonstrate that TIL are triggered by conjugate formation in that the TCR, p56lck, CD3zeta, LFA-1, lipid rafts, ZAP70, and linker for activation of T cells localize at the TIL:tumor cell contact site, and CD43 and CD45 are excluded. However, proximal TCR signaling is blocked upon conjugate formation because the inhibitory motif of p56lck is rapidly phosphorylated (Y505) and COOH-terminal Src kinase is recruited to the contact site, while Src homology 2 domain-containing protein phosphatase 2 is cytoplasmic. Our data support a novel mechanism explaining how tumor-induced inactivation of proximal TCR signaling regulates lytic function of antitumor T cells.
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MESH Headings
- Actins/deficiency
- Actins/metabolism
- Animals
- CD2 Antigens/metabolism
- CD3 Complex/metabolism
- CD8 Antigens/metabolism
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/metabolism
- CD8-Positive T-Lymphocytes/pathology
- Calcium/metabolism
- Cell Line, Tumor
- Cell Separation
- Cytoplasmic Granules/immunology
- Cytoplasmic Granules/metabolism
- Cytotoxicity, Immunologic
- Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors
- Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism
- Lymphocytes, Tumor-Infiltrating/enzymology
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/metabolism
- Lymphocytes, Tumor-Infiltrating/pathology
- Male
- Mice
- Mice, Inbred C57BL
- Phosphorylation
- Phosphotyrosine/metabolism
- Protein Transport/immunology
- Protein-Tyrosine Kinases/deficiency
- Protein-Tyrosine Kinases/metabolism
- Receptor-CD3 Complex, Antigen, T-Cell/metabolism
- Receptors, Antigen, T-Cell/deficiency
- Receptors, Antigen, T-Cell/physiology
- Signal Transduction/immunology
- ZAP-70 Protein-Tyrosine Kinase
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Affiliation(s)
- Mythili Koneru
- Department of Cell Biology and Kaplan Cancer Center, New York University School of Medicine, New York, NY 10016, USA
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27
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Coombs D, Dembo M, Wofsy C, Goldstein B. Equilibrium thermodynamics of cell-cell adhesion mediated by multiple ligand-receptor pairs. Biophys J 2004; 86:1408-23. [PMID: 14990470 PMCID: PMC1303978 DOI: 10.1016/s0006-3495(04)74211-3] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
In many situations, cell-cell adhesion is mediated by multiple ligand-receptor pairs. For example, the interaction between T cells and antigen-presenting cells of the immune system is mediated not only by T cell receptors and their ligands (peptide-major histocompatibility complex) but also by binding of intracellular adhesion molecules. Interestingly, these binding pairs have different resting lengths. Fluorescent labeling reveals segregation of the longer adhesion molecules from the shorter T cell receptors in this case. Here, we explore the thermal equilibrium of a general cell-cell interaction mediated by two ligand-receptor pairs to examine competition between the elasticity of the cell wall, nonspecific intercellular repulsion, and bond formation, leading to segregation of bonds of different lengths at equilibrium. We make detailed predictions concerning the relationship between physical properties of the membrane and ligand-receptor pairs and equilibrium pattern formation, and suggest experiments to refine our understanding of the system. We demonstrate our model by application to the T cell/antigen-presenting-cell system and outline applications to natural killer cell adhesion.
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Affiliation(s)
- Daniel Coombs
- Department of Mathematics, University of British Columbia, Vancouver, British Columbia V6T 1Z2, Canada.
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28
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Abstract
Supported intermembrane junctions, formed by rupture of giant unilamellar vesicles onto conventional supported lipid membranes, have recently emerged as model systems for the study of biochemical processes at membrane interfaces. Using intermembrane fluorescence resonance energy transfer and optical standing wave fluorescence interferometry, we characterize the nanometer-scale topography of supported intermembrane junctions and find two distinct association states. In one state, the two membranes adhere in close apposition, with intermembrane separations of a few nanometers. In the second state, large intermembrane spacings of approximately 50 nm are maintained by a balance between Helfrich (entropic) repulsion and occasional sites of tight adhesion that pin the two membranes together. Reversible transitions between these two states can be triggered with temperature changes. We further examine the physical properties of membranes in each state using a membrane mixture near its miscibility phase transition temperature. Thermodynamic characteristics of the phase transition and diffusive mobility of individual lipids are comparable. However, collective Brownian motion of phase-separated domains and compositional fluctuations are substantially modulated by intermembrane spacing. The scaling properties of diffusion coefficient with particle size are determined from detailed analysis of domain motion in the different junction types. The results provide experimental verification of a theoretical model for two-dimensional mobility in membranes, which includes frictional coupling across an interstitial water layer.
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Affiliation(s)
- Yoshihisa Kaizuka
- Department of Chemistry, University of California, Berkeley, California 94720, USA
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29
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Alpan O, Bachelder E, Isil E, Arnheiter H, Matzinger P. 'Educated' dendritic cells act as messengers from memory to naive T helper cells. Nat Immunol 2004; 5:615-22. [PMID: 15156140 DOI: 10.1038/ni1077] [Citation(s) in RCA: 106] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2004] [Accepted: 04/15/2004] [Indexed: 11/08/2022]
Abstract
Ingested antigens lead to the generation of effector T cells that secrete interleukin 4 (IL-4) rather than interferon-gamma (IFN-gamma) and are capable of influencing naive T cells in their immediate environment to do the same. Using chimeric mice generated by aggregation of two genotypically different embryos, we found that the conversion of a naive T cell occurs only if it can interact with the same antigen-presenting cell, although not necessarily the same antigen, as the effector T cell. Using a two-step culture system in vitro, we found that antigen-presenting dendritic cells can act as 'temporal bridges' to relay information from orally immunized memory CD4 T cells to naive CD4 T cells. The orally immunized T cells use IL-4 and IL-10 (but not CD40 ligand) to 'educate' dendritic cells, which in turn induce naive T cells to produce the same cytokines as those produced by the orally immunized memory T cells.
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Affiliation(s)
- Oral Alpan
- Ghost Lab, Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
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30
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Zitvogel L, Casares N, Péquignot MO, Chaput N, Albert ML, Kroemer G. Immune response against dying tumor cells. Adv Immunol 2004; 84:131-79. [PMID: 15246252 DOI: 10.1016/s0065-2776(04)84004-5] [Citation(s) in RCA: 99] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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31
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Heine H. Periphere Schmerzverarbeitung an Gelenken durch Akupunktur – Bedeutung des Parasympathikus. DEUTSCHE ZEITSCHRIFT FUR AKUPUNKTUR 2004. [DOI: 10.1078/0415-6412-00068] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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32
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Wong AW, Brickey WJ, Taxman DJ, van Deventer HW, Reed W, Gao JX, Zheng P, Liu Y, Li P, Blum JS, McKinnon KP, Ting JPY. CIITA-regulated plexin-A1 affects T-cell-dendritic cell interactions. Nat Immunol 2003; 4:891-8. [PMID: 12910265 DOI: 10.1038/ni960] [Citation(s) in RCA: 118] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2002] [Accepted: 07/08/2003] [Indexed: 11/09/2022]
Abstract
The major histocompatibility complex (MHC) class II transactivator (CIITA) is the 'master coactivator' of MHC class II genes. To identify new targets of CIITA, we analyzed cDNA microarrays of dendritic cells (DCs) from CIITA-deficient, MHC class II-deficient and control mice. We found the semaphorin receptor plexin-A1 was expressed in DCs, but not in other immune cells, and was strongly induced by CIITA. RNA interference by short hairpin RNA specific for plexin-A1, but not a single-nucleotide mutant, greatly reduced plexin-A1 expression and T cell stimulation by protein- or peptide-antigen-pulsed DCs.Plexin-A1 is not required for peptide binding to MHC. These data indicate involvement of plexin-A1 in T cell-DC interactions but not antigen processing or binding.
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MESH Headings
- Animals
- Base Sequence
- Cell Communication/immunology
- Crosses, Genetic
- DNA, Complementary/chemistry
- DNA, Complementary/genetics
- Dendritic Cells/cytology
- Dendritic Cells/immunology
- Down-Regulation/immunology
- Flow Cytometry
- Genes, MHC Class II
- Lymphocyte Activation/immunology
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Inbred DBA
- Mice, Knockout
- Molecular Sequence Data
- Nerve Tissue Proteins/genetics
- Nerve Tissue Proteins/immunology
- Nuclear Proteins
- Oligonucleotide Array Sequence Analysis
- Promoter Regions, Genetic
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/immunology
- T-Lymphocytes/cytology
- T-Lymphocytes/immunology
- Trans-Activators/immunology
- Transcriptional Activation/immunology
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Affiliation(s)
- Athena W Wong
- Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA
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33
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Abstract
Over the past decade, key protein interactions contributing to T cell antigen recognition have been characterized in molecular detail. These have included interactions involving the T cell antigen receptor (TCR) itself, its coreceptors CD4 and CD8, the accessory molecule CD2, and the costimulatory receptors CD28 and CTLA-4. A clear view is emerging of how these molecules interact with their ligands at the cell-cell interface. Structural and binding studies have confirmed that the proteins span small but comparable distances and that, overall, they interact very weakly. However, there have been important surprises as well: that TCR interactions with peptide-MHC are topologically constrained and characterized by considerable conformational flexibility at the binding interface; that coreceptors engage peptide-MHC with extraordinarily fast kinetics and at angles apparently precluding direct interactions with the TCR bound to the same peptide-MHC; that the structural mechanisms allowing recognition by costimulatory and accessory molecules to be weak and yet specific are very heterogeneous; and that because of differences in both binding affinity and stoichiometry, there is enormous variation in the stability of the various costimulatory receptor/ligand complexes. These studies provide the necessary framework for exploring how these molecular interactions initiate T cell activation.
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34
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Abstract
Understanding the regulatory events involved in the activation and inactivation of T cells is crucial to develop therapeutic approaches for autoimmune diseases and for organ transplantation. Co-stimulatory signals delivered through the CD28 receptor and inhibitory signals through CTLA-4 are required for the proper modulation of T cell responses and the induction and maintenance of peripheral tolerance. Manipulation of these signals is emerging as a potential strategy to prevent allograft rejection in different animal models. Recent data on the compartmentalization and the structural features of CTLA-4 within T cells provides critical information not only on the molecular basis of T cell inactivation by CTLA-4, but also on the key requirements for the successful development of therapeutic strategies targeting this molecule.
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Affiliation(s)
- Miren L Baroja
- The John P. Robarts Research Institute, Department of Microbiology, The University of Western Ontario, London, Ontario, Canada N6A 5K8
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35
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McBride JM, Fathman CG. A complicated relationship: fulfilling the interactive needs of the T lymphocyte and the dendritic cell. THE PHARMACOGENOMICS JOURNAL 2003; 2:367-76. [PMID: 12629502 DOI: 10.1038/sj.tpj.6500145] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2002] [Revised: 10/03/2002] [Accepted: 10/10/2002] [Indexed: 01/22/2023]
Abstract
T cells recognize antigenic peptides displayed on the surface of MHC-bearing antigen-presenting cells (APCs), and with sufficient costimulation become activated. However, the ability of an APC (even bearing the correct peptide) to initiate and fulfill the requirements for T cell activation is not easily achieved. Naive T cells use multiple copies of a single receptor to survey the vast array of peptides presented on an APC, and require multiple receptor engagements to initiate T cell activation. Dendritic cells (DCs) are specialized cells with optimal capabilities for priming naive CD4+ T cells. Activation occurs, after initial antigen recognition by T cells, followed by a rapid dialogue between the T cells and the DCs. The resulting changes in both the cytoskeleton and the expression or regulation of cell-surface molecules on both cell types act to further strengthen engagement. In this report, we review the fundamentals of CD4+ T helper cell : DC interactions and discuss recent data concerning the molecular characteristics of this engagement.
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Affiliation(s)
- J M McBride
- Department of Medicine, Division of Immunology, Stanford University School of Medicine, Palo Alto, CA, USA
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36
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Ribas A, Butterfield LH, Glaspy JA, Economou JS. Current developments in cancer vaccines and cellular immunotherapy. J Clin Oncol 2003; 21:2415-32. [PMID: 12805342 DOI: 10.1200/jco.2003.06.041] [Citation(s) in RCA: 246] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
This article reviews the immunologic basis of clinical trials that test means of tumor antigen recognition and immune activation, with the goal to provide the clinician with a mechanistic understanding of ongoing cancer vaccine and cellular immunotherapy clinical trials. Multiple novel immunotherapy strategies have reached the stage of testing in clinical trials that were accelerated by recent advances in the characterization of tumor antigens and by a more precise knowledge of the regulation of cell-mediated immune responses. The key steps in the generation of an immune response to cancer cells include loading of tumor antigens onto antigen-presenting cells in vitro or in vivo, presenting antigen in the appropriate immune stimulatory environment, activating cytotoxic lymphocytes, and blocking autoregulatory control mechanisms. This knowledge has opened the door to antigen-specific immunization for cancer using tumor-derived proteins or RNA, or synthetically generated peptide epitopes, RNA, or DNA. The critical step of antigen presentation has been facilitated by the coadministration of powerful immunologic adjuvants, the provision of costimulatory molecules and immune stimulatory cytokines, and the ability to culture dendritic cells. Advances in the understanding of the nature of tumor antigens and their optimal presentation, and in the regulatory mechanisms that govern the immune system, have provided multiple novel immunotherapy intervention strategies that are being tested in clinical trials.
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Affiliation(s)
- Antoni Ribas
- Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, 90095-1782, USA.
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37
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Abstract
Immunological synapses (ISs) are specialised signalling domains characterised by complex molecular clustering and segregation at the contact site between cells of the immune system. T lymphocytes form different ISs depending on their state of activation and on the antigen-presenting cells with which they interact. The structural features of the various ISs are better established than the functions they carry out. Recent advances point to the importance of taking into account diversity in both the structures and the functions of IS.
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Affiliation(s)
- Alain Trautmann
- Départment de Biologie Cellulaire, Institut COCHIN, Institut National de la santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, 22, rue Méchain 75014, Paris, France
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38
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Bauer B, Jenny M, Fresser F, Uberall F, Baier G. AKT1/PKBalpha is recruited to lipid rafts and activated downstream of PKC isotypes in CD3-induced T cell signaling. FEBS Lett 2003; 541:155-62. [PMID: 12706837 DOI: 10.1016/s0014-5793(03)00287-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Protein kinase (PK) Ctheta and Akt/PKBalpha cooperate in T cell receptor/CD28-induced T cell signaling. We here demonstrate the recruitment of endogenous Akt1 and PKCtheta to lipid rafts in CD3-stimulated T cells. Further we show that Myr-PKCtheta mediates translocation of endogenous Akt1 to the plasma membrane as well as to lipid rafts, most likely explained by the observed complex formation of both protein kinases. In addition, in peripheral mouse T cells, the PKC inhibitor Gö6850 could partially block Akt1 activation in CD3-induced signaling, placing PKC isotype(s) upstream of Akt1. However, T cells derived from PKCtheta knockout mice were not impaired in CD3- or phorbol ester-induced Akt1 activity. Taken together, the results of this study give new insights into the functional link of Akt1 and PKCtheta in T cell signaling, demonstrating the co-recruitment of the two kinases and showing a novel pathway leading to Akt1 transactivation where PKC isotype(s) are involved but PKCtheta is not essential.
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Affiliation(s)
- Birgit Bauer
- Department of Medical Biology and Human Genetics, University of Innsbruck, Austria
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39
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Anderson ME, Siahaan TJ. Targeting ICAM-1/LFA-1 interaction for controlling autoimmune diseases: designing peptide and small molecule inhibitors. Peptides 2003; 24:487-501. [PMID: 12732350 DOI: 10.1016/s0196-9781(03)00083-4] [Citation(s) in RCA: 105] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
This review describes the role of modulation of intracellular adhesion molecule-1 (ICAM-1)/leukocyte function-associated antigen-1 (LFA-1) interaction in controlling autoimmune diseases or inducing immunotolerance. ICAM-1/LFA-1 interaction is essential for T-cell activation as well as for migration of T-cells to target tissues. This interaction also functions, along with Signal-1, as a co-stimulatory signal (Signal-2) for T-cell activation, which is delivered by the T-cell receptors (TCR)-major histocompatibility complex (MHC)-peptide complex. Therefore, blocking ICAM-1/LFA-1 interaction can suppress T-cell activation in autoimmune diseases and organ transplantation. Many types of inhibitors (i.e. antibodies, peptides, small molecules) have been developed to block ICAM-1/LFA-1 interactions, and some of these molecules have reached clinical trials. Peptides derived from ICAM-1 and LFA-1 sequences have been shown to inhibit T-cell adhesion and activation. In addition, these inhibitors have been useful in elucidating the mechanism of ICAM-1/LFA-1 interaction. Besides binding to LFA-1, the ICAM-1 peptide can be internalized by LFA-1 receptors into the cytoplasmic domain of T-cells. Therefore, this ICAM-1 peptide can be utilized to selectively target toxic drugs to T-cells, thus avoiding harmful side effects. Finally, bi-functional inhibitory peptide (BPI), which is made by conjugating the antigenic peptide and an LFA-1 peptide, can alter the T-cell commitment from T-helper-1 (Th1) to T-helper-2 (Th2)-like cells, suggesting that this peptide may have a role in blocking the formation of the "immunological synapse."
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Affiliation(s)
- Meagan E Anderson
- Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Avenue, Lawrence, KS 66047, USA
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40
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Davis SJ, Ikemizu S, Evans EJ, Fugger L, Bakker TR, van der Merwe PA. The nature of molecular recognition by T cells. Nat Immunol 2003; 4:217-24. [PMID: 12605231 DOI: 10.1038/ni0303-217] [Citation(s) in RCA: 169] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Considerable progress has been made in characterizing four key sets of interactions controlling antigen responsiveness in T cells, involving the following: the T cell antigen receptor, its coreceptors CD4 and CD8, the costimulatory receptors CD28 and CTLA-4, and the accessory molecule CD2. Complementary work has defined the general biophysical properties of interactions between cell surface molecules. Among the major conclusions are that these interactions are structurally heterogeneous, often reflecting clear-cut functional constraints, and that, although they all interact relatively weakly, hierarchical differences in the stabilities of the signaling complexes formed by these molecules may influence the sequence of steps leading to T cell activation. Here we review these developments and highlight the major challenges remaining as the field moves toward formulating quantitative models of T cell recognition.
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Affiliation(s)
- Simon J Davis
- Nuffield Department of Clinical Medicine, Weatherall Institute of Molecular Medicine, The University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK.
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41
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Samstag Y, Eibert SM, Klemke M, Wabnitz GH. Actin cytoskeletal dynamics in T lymphocyte activation and migration. J Leukoc Biol 2003; 73:30-48. [PMID: 12525560 DOI: 10.1189/jlb.0602272] [Citation(s) in RCA: 141] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Dynamic rearrangements of the actin cytoskeleton are crucial for the function of numerous cellular elements including T lymphocytes. They are required for migration of T lymphocytes through the body to scan for the presence of antigens, as well as for the formation and stabilization of the immunological synapse at the interface between antigen-presenting cells and T lymphocytes. Supramolecular activation clusters within the immunological synapse play an important role for the initiation of T cell responses and for the execution of T cell effector functions. In addition to the T cell receptor/CD3 induced actin nucleation via Wasp/Arp2/3-activation, signals through accessory receptors of the T cell (i.e., costimulation) regulate actin cytoskeletal dynamics. In this regard, the actin-binding proteins cofilin and L-plastin represent prominent candidates linking accessory receptor stimulation to the rearrangement of the actin cytoskeleton. Cofilin enhances actin polymerization via its actin-severing activity, and as a long-lasting effect, cofilin generates novel actin monomers through F-actin depolymerization. L-plastin stabilizes actin filament structures by means of its actin-bundling activity.
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Affiliation(s)
- Yvonne Samstag
- Institute for Immunology, Ruprecht-Karls-University, Im Neuenheimer Feld 305, D-69120 Heidelberg, Germany.
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42
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Moldovan MC, Yachou A, Lévesque K, Wu H, Hendrickson WA, Cohen EA, Sékaly RP. CD4 dimers constitute the functional component required for T cell activation. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2002; 169:6261-8. [PMID: 12444132 DOI: 10.4049/jimmunol.169.11.6261] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The CD4 molecule plays a key role in the development and activation of helper T cells. Dimerization and oligomerization is often a necessary step in the function of several cell surface receptors. Herein, we provide direct biochemical evidence confirming the presence of CD4 as dimers in transfected cells from hemopoetic and fibroblastic origin as well as in primary T cells. Such dimers are also observed with murine CD4 confirming selective pressure during evolution to maintain such a structure. Using a series of point mutations, we have precisely mapped the dimerization site at residues K318 and Q344 within the fourth extracellular domain of CD4. These residues are highly conserved and their mutation results in interference with dimer formation. More importantly, we demonstrate that dimer formation is essential for the coligand and coreceptor functions of CD4 in T cell activation. These data strongly suggest that CD4 dimerization is necessary for helper T cell function.
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Costello PS, Gallagher M, Cantrell DA. Sustained and dynamic inositol lipid metabolism inside and outside the immunological synapse. Nat Immunol 2002; 3:1082-9. [PMID: 12389042 DOI: 10.1038/ni848] [Citation(s) in RCA: 176] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2002] [Accepted: 08/27/2002] [Indexed: 01/14/2023]
Abstract
T cell activation is triggered by several hours of contact with peptide-major histocompatibility (MHC) complexes on the surface of antigen-presenting cells (APCs). The nature and location of the sustained signal transduction pathways required for T cell activation are unknown. We show here that the production of phosphatidylinositol(3,4,5)triphosphate (PIP3) was dynamically sustained for hours as T cells responded to antigen. In addition, sustained elevation of PIP3 was essential for T cell proliferation. There was PIP3 accumulation in the T cell-APC contact zone and at the antipodal pole of the cell. The immune synapse is thus not the sole site of sustained signal transduction in activated T cells.
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Affiliation(s)
- Patrick S Costello
- Lymphocyte Activation Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
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44
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Wong AP, Groves JT. Molecular topography imaging by intermembrane fluorescence resonance energy transfer. Proc Natl Acad Sci U S A 2002; 99:14147-52. [PMID: 12391328 PMCID: PMC137852 DOI: 10.1073/pnas.212392599] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Fluorescence resonance energy transfer (FRET) between lipid-linked donor and acceptor molecules in two apposing lipid bilayer membranes is used to resolve topographical features at an intermembrane junction. Efficient energy transfer occurs when the membranes are apposed closely, which creates an image, or footprint, that maps the contact zone and reveals nanometer-scale topographical structures. We experimentally characterize intermembrane FRET by using a supported membrane junction consisting of a glass-supported lipid membrane, onto which a second membrane is deposited by rupture of a giant vesicle. A series of membrane junctions containing different glycolipids (phosphatidylinositol and ganglioside G(M1)), protein (cholera toxin), and lipid-linked polyethylene glycol are studied. The carbohydrate and protein components influence the intermembrane separation. Differential FRET efficiency is clearly distinguishable for each case. Quantitative analysis of the FRET efficiency yields measurements of intermembrane-separation distances that agree precisely with structural data on G(M1) and cholera toxin. The lateral arrangement of molecular species on the membrane surface thus can be discerned by their influence on membrane spacing without the need for direct labeling of the molecule of interest. In the case of polyethylene glycol lipid-containing membrane junctions, imaging by intermembrane FRET reveals spontaneously forming patterns that are not visible in conventional fluorescence images.
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Affiliation(s)
- Amy P Wong
- Department of Chemistry, University of California, Berkeley, CA 94720, USA
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45
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Paratcha G, Ibáñez CF. Lipid rafts and the control of neurotrophic factor signaling in the nervous system: variations on a theme. Curr Opin Neurobiol 2002; 12:542-9. [PMID: 12367633 DOI: 10.1016/s0959-4388(02)00363-x] [Citation(s) in RCA: 86] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Lipid rafts are specialized, liquid-ordered subdomains of the plasma membrane. Through their ability to promote specific compartmentalization of lipids and membrane proteins, lipid rafts have emerged as membrane platforms specialized for signal transduction. In recent years, signaling by neurotrophic factors and their receptors has been shown to depend upon the integrity and function of lipid rafts and associated components. It has also been shown that these microdomains play critical roles in selective axon-dendritic sorting and the proteolytic processing of several neurotrophic ligands and receptors in neuronal cells. The available evidence supports an important role for lipid rafts in the initiation, propagation and maintenance of signal transduction events triggered by different neurotrophic factors and their receptors in the nervous system.
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Affiliation(s)
- Gustavo Paratcha
- Division of Molecular Neurobiology, Department of Neuroscience, Karolinska Institute, Retzius väg 8, A2:2, Stockholm, Sweden.
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46
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Lee SJE, Hori Y, Groves JT, Dustin ML, Chakraborty AK. Correlation of a dynamic model for immunological synapse formation with effector functions: two pathways to synapse formation. Trends Immunol 2002; 23:492-9. [PMID: 12297421 DOI: 10.1016/s1471-4906(02)02285-8] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
During antigen recognition by T cells different receptors and ligands form a pattern in the intercellular junction called the immunological synapse, which might be involved in T-cell activation. Recently, a synapse assembly model has been proposed, which enables the calculation of the propensity for synapse assembly driven by membrane-constrained protein binding interactions. We bring together model predictions of mature synapse assembly with data on the dependence of T-cell responses on T-cell receptor (TCR)-MHC-peptide (pMHC) binding kinetics. Predictions of mature synapse assembly, based on TCR-pMHC binding kinetics, correlate well with observed cytokine responses by T cells bearing the relevant TCR but not with cytotoxic T lymphocyte-mediated killing. We discuss the suggested different role for the synapse in pre- and post-nuclear activation events in T cells. The view of immunological synapse assembly given here emphasizes the importance of both the on and off rates for the TCR-pMHC interaction and in this context recent data on a positive role for analogs of self-peptides in synapse assembly is considered.
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Affiliation(s)
- Sung-Joo E Lee
- Biophysics Graduate Group, Dept of Chemistry, University of California, Berkeley, CA, USA
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47
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Gao GF, Rao Z, Bell JI. Molecular coordination of alphabeta T-cell receptors and coreceptors CD8 and CD4 in their recognition of peptide-MHC ligands. Trends Immunol 2002; 23:408-13. [PMID: 12133804 DOI: 10.1016/s1471-4906(02)02282-2] [Citation(s) in RCA: 98] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The interaction of the alphabeta T-cell receptor (TCR) with its ligand, peptide-MHC (pMHC), is enhanced by the recognition of the coreceptor CD8 or CD4 to the same pMHC in the immunological synapse. In the past few years, the coordination of these interactions at the molecular level has been revealed by analysis of their complex crystal structures and binding dynamics. Here we discuss the interactions of pMHC with the TCR and coreceptor CD8 or CD4 on the surfaces of alphabeta T cells and antigen presenting cells, and the implications for TCR signalling and the T-cell repertoire.
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Affiliation(s)
- George F Gao
- Nuffield Dept. of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Headington, Oxford, UK.
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48
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Morford LA, Forrest K, Logan B, Overstreet LK, Goebel J, Brooks WH, Roszman TL. Calpain II colocalizes with detergent-insoluble rafts on human and Jurkat T-cells. Biochem Biophys Res Commun 2002; 295:540-6. [PMID: 12150984 DOI: 10.1016/s0006-291x(02)00676-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Calpain, a calcium-dependent cysteine protease, is known to associate with the T-cell plasma membrane and subsequently cleave a number of cytoskeletal-associated proteins. In this study, we report the novel observation that calpain II, but not calpain I, associates with membrane lipid rafts on human peripheral blood T-cells and Jurkat cells. Raft-associated calpain activity is enhanced with exogenous calcium and inhibited with calpeptin, a specific inhibitor of calpain activity. In addition, we demonstrate that calpain cleaves the cytoskeletal-associated protein, talin, during the first 30-min after cell stimulation. We propose that lipid raft associated-calpain II could function in early TCR signaling to facilitate immune synapse formation through cytoskeletal remodeling mechanisms. Hence, we demonstrate that the positioning of calpain II within T-cell lipid rafts strategically places it in close proximity to known calpain substrates that are cleaved during Ag-specific T-cell signaling and immune synapse formation.
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Affiliation(s)
- Lorri A Morford
- Department of Microbiology and Immunology, University of Kentucky, Lexington, KY 40536-0298, USA
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49
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Huang J, Lo PF, Zal T, Gascoigne NRJ, Smith BA, Levin SD, Grey HM. CD28 plays a critical role in the segregation of PKC theta within the immunologic synapse. Proc Natl Acad Sci U S A 2002; 99:9369-73. [PMID: 12077322 PMCID: PMC123147 DOI: 10.1073/pnas.142298399] [Citation(s) in RCA: 116] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/17/2002] [Indexed: 11/18/2022] Open
Abstract
The signaling pathways that lead to the localization of cellular protein to the area of interaction between T cell and antigen-presenting cell and the mechanism by which these molecules are further sorted to the peripheral supramolecular activation cluster or central supramolecular activation cluster regions of the immunologic synapse are poorly understood. In this study, we investigated the functional involvement of CD28 costimulation in the T cell receptor (TCR)-mediated immunologic synapse formation with respect to protein kinase C (PKC)theta; localization. We showed that CD3 crosslinking alone was sufficient to induce PKC theta; capping in naive CD4(+) T cells. Studies with pharmacologic inhibitors and knockout mice showed that the TCR-derived signaling that drives PKC theta; membrane translocation requires the Src family kinase, Lck, but not Fyn. In addition, a time course study of the persistence of T cell molecules to the immunologic synapse indicated that PKC theta;, unlike TCR, persisted in the synapse for at least 4 h, a time that is sufficient for commitment of a T cell to cell division. Finally, by using TCR-transgenic T cells from either wild-type or CD28-deficient mice, we showed that CD28 expression was required for the formation of the mature immunologic synapse, because antigen stimulation of CD28(-) T cells led to a diffuse pattern of localization of PKC theta; and lymphocyte function-associated antigen-1 in the immunologic synapse, in contrast to the central supramolecular activation cluster localization of PKC theta; in CD28(+) T cells.
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Affiliation(s)
- Jianyong Huang
- Division of Immunochemistry, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121, USA
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Abstract
Less than five years ago it was reported that cell surface molecules at the contact site between CD4 T cells and antigen-presenting cells redistribute into distinct patterns, forming an organized interface termed the immunological synapse. More recently, similar reorganized interfaces have been observed with CD8 T cells and NK cells, suggesting that they may be a common feature of lymphocyte activation. Although there has been some advance in our understanding of the mechanisms underlying this redistribution, its purpose remains unclear and controversial.
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