Key Points
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In vitro clonal T-cell anergy is induced in previously activated T cells or T-cell clones by restimulation through the T-cell receptor (TCR) in the absence of co-stimulatory signals. This suboptimal signalling produces long-lived effects, such as reduced proliferation and cytokine production.
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Early molecular studies of anergic T cells found reduced amounts of the activator protein 1 (AP1) heterodimer in the nucleus coupled with normal translocation to the nucleus of nuclear factor of activated T cells (NFAT). Subsequent evidence suggested the requirement for calcium flux and the potential for expression of proteins enriched specifically by the anergic programme to induce T-cell anergy.
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Recent work identified important roles for linker for activation of T cells (LAT) palmitoylation, diacylglycerol (DAG) signalling, and transcription factors for the induction of both in vitro and in vivo T-cell anergy.
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Using the calcium ionophore ionomycin to simulate calcium flux and promote NFAT nuclear translocation without co-stimulation events, a group of E3 ubiquitin ligases — Casitas B-lineage lymphoma B (CBL-B), gene related to anergy in lymphocytes (GRAIL) and ITCH (itchy homologue E3 ubiquitin protein ligase) — were found to be enriched in anergic T cells. These members of the ubiquitin–proteasome pathway were also identified in other model systems of in vitro and in vivo T-cell anergy, and their ability to induce T-cell anergy depends on their E3 ubiquitin ligase activity.
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CBL-B ubiquitylation affects various signalling pathways including the phosphoinositide 3-kinase (PI3K) pathway, VAV1-mediated actin reorganization, and TCR downregulation. GRAIL-mediated ubiquitylation stabilizes expression of an inhibitor of the RHO family and has potent effects on T-cell activation. ITCH expression attenuates phospholipase Cγ1 (PLCγ1) activation by monoubiquitylation and targets the JUN family of transcription factors for degradation.
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As these E3 ubiquitin ligases contain disparate structural elements, subcellular localization and substrate targets, it is likely that they function at different levels of T-cell activation. Combining their effects together in an additive manner shunts T cells away from activation and towards T-cell anergy.
Abstract
Directing both innate and adaptive immune responses against foreign pathogens with correct timing, location and specificity is a fundamental objective for the immune system. Full activation of CD4+ T cells requires the binding of peptide–MHC complexes coupled with accessory signals provided by the antigen-presenting cell. However, aberrant activation of the T-cell receptor alone in mature T cells can produce a long-lived state of functional unresponsiveness, known as anergy. Recent studies probing both immune signalling pathways and the ubiquitin–proteasome system have helped to refine and elaborate current models for the molecular mechanisms underlying T-cell anergy. Controlling anergy induction and maintenance will be a key component in the future to mitigate unwanted T-cell activation that leads to autoimmune disease.
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References
Kronenberg, M. & Rudensky, A. Regulation of immunity by self-reactive T cells. Nature 435, 598–604 (2005).
Rathmell, J. C. & Thompson, C. B. Pathways of apoptosis in lymphocyte development, homeostasis, and disease. Cell 109, S97–S107 (2002).
Starr, T. K., Jameson, S. C. & Hogquist, K. A. Positive and negative selection of T cells. Annu. Rev. Immunol. 21, 139–176 (2003).
Jenkins, M. K., Pardoll, D. M., Mizuguchi, J., Quill, H. & Schwartz, R. H. T-cell unresponsiveness in vivo and in vitro: fine specificity of induction and molecular characterization of the unresponsive state. Immunol. Rev. 95, 113–135 (1987).
Schwartz, R. H. T cell anergy. Annu. Rev. Immunol. 21, 305–334 (2003). An outstanding in-depth review about the experiments used to originally identify and define both clonal T-cell anergy and adaptive tolerance.
Jenkins, M. K., Pardoll, D. M., Mizuguchi, J., Chused, T. M. & Schwartz, R. H. Molecular events in the induction of a nonresponsive state in interleukin 2-producing helper T-lymphocyte clones. Proc. Natl Acad. Sci. USA 84, 5409–5413 (1987).
Quill, H. & Schwartz, R. H. Stimulation of normal inducer T cell clones with antigen presented by purified Ia molecules in planar lipid membranes: specific induction of a long-lived state of proliferative nonresponsiveness. J. Immunol. 138, 3704–3712 (1987).
Jenkins, M. K., Chen, C. A., Jung, G., Mueller, D. L. & Schwartz, R. H. Inhibition of antigen-specific proliferation of type 1 murine T cell clones after stimulation with immobilized anti-CD3 monoclonal antibody. J. Immunol. 144, 16–22 (1990).
Hargreaves, R. G. et al. Dissociation of T cell anergy from apoptosis by blockade of Fas/Apo-1 (CD95) signaling. J. Immunol. 158, 3099–3107 (1997).
Beverly, B., Kang, S. M., Lenardo, M. J. & Schwartz, R. H. Reversal of in vitro T cell clonal anergy by IL-2 stimulation. Int. Immunol. 4, 661–671 (1992).
Kang, S. M. et al. Transactivation by AP-1 is a molecular target of T cell clonal anergy. Science 257, 1134–1138 (1992).
Fields, P. E., Gajewski, T. F. & Fitch, F. W. Blocked Ras activation in anergic CD4+ T cells. Science 271, 1276–1278 (1996).
Li, W., Whaley, C. D., Mondino, A. & Mueller, D. L. Blocked signal transduction to the ERK and JNK protein kinases in anergic CD4+ T cells. Science 271, 1272–1276 (1996).
DeSilva, D. R., Feeser, W. S., Tancula, E. J. & Scherle, P. A. Anergic T cells are defective in both jun NH2-terminal kinase and mitogen-activated protein kinase signaling pathways. J. Exp. Med. 183, 2017–2023 (1996).
Lyakh, L., Ghosh, P. & Rice, N. R. Expression of NFAT-family proteins in normal human T cells. Mol. Cell. Biol. 17, 2475–2484 (1997).
Chai, J. G. & Lechler, R. I. Immobilized anti-CD3 mAb induces anergy in murine naive and memory CD4+ T cells in vitro. Int. Immunol. 9, 935–944 (1997).
Hayashi, R. J., Loh, D. Y., Kanagawa, O. & Wang, F. Differences between responses of naive and activated T cells to anergy induction. J. Immunol. 160, 33–38 (1998).
Su, B. et al. JNK is involved in signal integration during costimulation of T lymphocytes. Cell 77, 727–736 (1994).
Telander, D. G., Malvey, E. N. & Mueller, D. L. Evidence for repression of IL-2 gene activation in anergic T cells. J. Immunol. 162, 1460–1465 (1999).
Ramsdell, F., Lantz, T. & Fowlkes, B. J. A nondeletional mechanism of thymic self tolerance. Science 246, 1038–1041 (1989).
Rellahan, B. L., Jones, L. A., Kruisbeek, A. M., Fry, A. M. & Matis, L. A. In vivo induction of anergy in peripheral Vβ8+ T cells by staphylococcal enterotoxin B. J. Exp. Med. 172, 1091–1100 (1990).
Kawabe, Y. & Ochi, A. Selective anergy of Vβ8+, CD4+ T cells in Staphylococcus enterotoxin B-primed mice. J. Exp. Med. 172, 1065–1070 (1990).
Pape, K. A., Merica, R., Mondino, A., Khoruts, A. & Jenkins, M. K. Direct evidence that functionally impaired CD4+ T cells persist in vivo following induction of peripheral tolerance. J. Immunol. 160, 4719–4729 (1998).
Lanoue, A., Bona, C., von Boehmer, H. & Sarukhan, A. Conditions that induce tolerance in mature CD4+ T cells. J. Exp. Med. 185, 405–414 (1997).
Rocha, B., Tanchot, C. & Von Boehmer, H. Clonal anergy blocks in vivo growth of mature T cells and can be reversed in the absence of antigen. J. Exp. Med. 177, 1517–1521 (1993).
Rocha, B., Grandien, A. & Freitas, A. A. Anergy and exhaustion are independent mechanisms of peripheral T cell tolerance. J. Exp. Med. 181, 993–1003 (1995).
Frauwirth, K. A., Alegre, M. L. & Thompson, C. B. Induction of T cell anergy in the absence of CTLA-4/B7 interaction. J. Immunol. 164, 2987–2993 (2000).
Perez, V. L. et al. Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement. Immunity 6, 411–417 (1997).
Downward, J., Graves, J. D., Warne, P. H., Rayter, S. & Cantrell, D. A. Stimulation of p21ras upon T-cell activation. Nature 346, 719–723 (1990).
Izquierdo, M., Downward, J., Graves, J. D. & Cantrell, D. A. Role of protein kinase C in T-cell antigen receptor regulation of p21ras: evidence that two p21ras regulatory pathways coexist in T cells. Mol. Cell. Biol. 12, 3305–3312 (1992).
Cullen, P. J. & Lockyer, P. J. Integration of calcium and Ras signalling. Nature Rev. Mol. Cell Biol. 3, 339–348 (2002).
Ebinu, J. O. et al. RasGRP, a Ras guanyl nucleotide-releasing protein with calcium- and diacylglycerol-binding motifs. Science 280, 1082–1086 (1998).
Bivona, T. G. et al. Phospholipase Cγ activates Ras on the Golgi apparatus by means of RasGRP1. Nature 424, 694–698 (2003).
Ebinu, J. O. et al. RasGRP links T-cell receptor signaling to Ras. Blood 95, 3199–3203 (2000).
Dower, N. A. et al. RasGRP is essential for mouse thymocyte differentiation and TCR signaling. Nature Immunol. 1, 317–321 (2000).
Olenchock, B. A. et al. Disruption of diacylglycerol metabolism impairs the induction of T cell anergy. Nature Immunol. 7, 1174–1181 (2006).
Zha, Y. et al. T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-α. Nature Immunol. 7, 1166–1173 (2006). References 36 and 37 describe the identification of attenuated DAG signalling due to its conversion to phosphatidic acid in multiple model systems of T-cell anergy.
Zhong, X. P. et al. Regulation of T cell receptor-induced activation of the Ras–ERK pathway by diacylglycerol kinase ζ. J. Biol. Chem. 277, 31089–31098 (2002).
Zhong, X. P. et al. Enhanced T cell responses due to diacylglycerol kinase ζ deficiency. Nature Immunol. 4, 882–890 (2003).
Macian, F. et al. Transcriptional mechanisms underlying lymphocyte tolerance. Cell 109, 719–731 (2002). This paper shows that the presence of NFAT in the nucleus, in the absence of the AP1 heterodimer, imparts an anergic gene-expression profile that is distinct from that seen during full T-cell activation.
Crespi, D. et al. Constitutive active p21ras enhances primary T cell responsiveness to Ca2+ signals without interfering with the induction of clonal anergy. Eur. J. Immunol. 32, 2500–2509 (2002).
Thiel, G. & Cibelli, G. Regulation of life and death by the zinc finger transcription factor Egr-1. J. Cell. Physiol. 193, 287–292 (2002).
Harris, J. E. et al. Early growth response gene-2, a zinc-finger transcription factor, is required for full induction of clonal anergy in CD4+ T cells. J. Immunol. 173, 7331–7338 (2004).
Safford, M. et al. Egr-2 and Egr-3 are negative regulators of T cell activation. Nature Immunol. 6, 472–480 (2005). This paper shows that EGR2 and EGR3 expression is associated with T-cell anergy and also contributes to T-cell anergy induction by upregulating the expression of CBL-B.
Houtman, J. C., Barda-Saad, M. & Samelson, L. E. Examining multiprotein signaling complexes from all angles. FEBS J. 272, 5426–5435 (2005).
Hundt, M. et al. Impaired activation and localization of LAT in anergic T cells as a consequence of a selective palmitoylation defect. Immunity 24, 513–522 (2006). This study shows attenuated LAT signalling due to altered palmitoylation and membrane relocalization in multiple systems of T-cell anergy.
Goldstein, G. et al. Isolation of a polypeptide that has lymphocyte-differentiating properties and is probably represented universally in living cells. Proc. Natl Acad. Sci. USA 72, 11–15 (1975).
Wilkinson, K. D., Urban, M. K. & Haas, A. L. Ubiquitin is the ATP-dependent proteolysis factor I of rabbit reticulocytes. J. Biol. Chem. 255, 7529–7532 (1980).
Pickart, C. M. & Fushman, D. Polyubiquitin chains: polymeric protein signals. Curr. Opin. Chem. Biol. 8, 610–616 (2004).
Tanaka, T., Soriano, M. A. & Grusby, M. J. SLIM is a nuclear ubiquitin E3 ligase that negatively regulates STAT signaling. Immunity 22, 729–736 (2005).
Liu, W. H. & Lai, M. Z. Deltex regulates T-cell activation by targeted degradation of active MEKK1. Mol. Cell. Biol. 25, 1367–1378 (2005).
Zhao, H. et al. A novel E3 ubiquitin ligase TRAC-1 positively regulates T cell activation. J. Immunol. 174, 5288–5297 (2005).
Vinuesa, C. G. et al. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435, 452–458 (2005).
Heissmeyer, V. et al. Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nature Immunol. 5, 255–265 (2004).
Anandasabapathy, N. et al. GRAIL: an E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4+ T cells. Immunity 18, 535–547 (2003). References 54, 55 and 69 describe for the first time the role of the E3 ubiquitin ligases CBL-B, GRAIL and ITCH in the induction of T-cell anergy.
Mueller, D. L. E3 ubiquitin ligases as T cell anergy factors. Nature Immunol. 5, 883–890 (2004).
Keane, M. M., Rivero-Lezcano, O. M., Mitchell, J. A., Robbins, K. C. & Lipkowitz, S. Cloning and characterization of Cbl-b: a SH3 binding protein with homology to the c-Cbl proto-oncogene. Oncogene 10, 2367–2377 (1995).
Elly, C. et al. Tyrosine phosphorylation and complex formation of Cbl-b upon T cell receptor stimulation. Oncogene 18, 1147–1156 (1999).
Bachmaier, K. et al. Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature 403, 211–216 (2000).
Chiang, Y. J. et al. Cbl-b regulates the CD28 dependence of T-cell activation. Nature 403, 216–220 (2000).
Li, D. et al. Cutting edge: Cbl-b: one of the key molecules tuning CD28- and CTLA-4-mediated T cell costimulation. J. Immunol. 173, 7135–7139 (2004).
Zhang, J. et al. Cutting edge: regulation of T cell activation threshold by CD28 costimulation through targeting Cbl-b for ubiquitination. J. Immunol. 169, 2236–2240 (2002).
Bustelo, X. R., Crespo, P., Lopez-Barahona, M., Gutkind, J. S. & Barbacid, M. Cbl-b, a member of the Sli-1/c-Cbl protein family, inhibits Vav-mediated c-Jun N-terminal kinase activation. Oncogene 15, 2511–2520 (1997).
Krawczyk, C. et al. Cbl-b is a negative regulator of receptor clustering and raft aggregation in T cells. Immunity 13, 463–473 (2000).
Viola, A., Schroeder, S., Sakakibara, Y. & Lanzavecchia, A. T lymphocyte costimulation mediated by reorganization of membrane microdomains. Science 283, 680–682 (1999).
Fang, D. & Liu, Y. C. Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells. Nature Immunol. 2, 870–875 (2001).
Fang, D. et al. Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells. J. Biol. Chem. 276, 4872–4878 (2001).
Han, J. et al. Role of substrates and products of PI 3-kinase in regulating activation of Rac-related guanosine triphosphatases by Vav. Science 279, 558–560 (1998).
Jeon, M. S. et al. Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction. Immunity 21, 167–177 (2004).
Jun, J. E. & Goodnow, C. C. Scaffolding of antigen receptors for immunogenic versus tolerogenic signaling. Nature Immunol. 4, 1057–1064 (2003).
Cenciarelli, C. et al. Activation-induced ubiquitination of the T cell antigen receptor. Science 257, 795–797 (1992).
Hou, D., Cenciarelli, C., Jensen, J. P., Nguygen, H. B. & Weissman, A. M. Activation-dependent ubiquitination of a T cell antigen receptor subunit on multiple intracellular lysines. J. Biol. Chem. 269, 14244–14247 (1994).
Cenciarelli, C., Wilhelm, K. G. Jr, Guo, A. & Weissman, A. M. T cell antigen receptor ubiquitination is a consequence of receptor-mediated tyrosine kinase activation. J. Biol. Chem. 271, 8709–8713 (1996).
Schonrich, G. et al. Down-regulation of T cell receptors on self-reactive T cells as a novel mechanism for extrathymic tolerance induction. Cell 65, 293–304 (1991).
Naramura, M., Kole, H. K., Hu, R. J. & Gu, H. Altered thymic positive selection and intracellular signals in Cbl-deficient mice. Proc. Natl Acad. Sci. USA 95, 15547–15552 (1998).
Thien, C. B. et al. Loss of c-Cbl RING finger function results in high-intensity TCR signaling and thymic deletion. EMBO J. 24, 3807–3819 (2005).
Naramura, M. et al. c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. Nature Immunol. 3, 1192–1199 (2002).
Huang, F. et al. Establishment of the major compatibility complex-dependent development of CD4+ and CD8+ T cells by the Cbl family proteins. Immunity 25, 571–581 (2006).
Seroogy, C. M. et al. The gene related to anergy in lymphocytes, an E3 ubiquitin ligase, is necessary for anergy induction in CD4 T cells. J. Immunol. 173, 79–85 (2004).
Borchers, A. G. et al. The E3 ubiquitin ligase GREUL1 anteriorizes ectoderm during Xenopus development. Dev. Biol. 251, 395–408 (2002).
Soares, L. et al. Two isoforms of otubain 1 regulate T cell anergy via GRAIL. Nature Immunol. 5, 45–54 (2004).
Su, L., Lineberry, N., Huh, Y., Soares, L. & Fathman, C. G. A novel E3 ubiquitin ligase substrate screen identifies Rho guanine dissociation inhibitor as a substrate of gene related to anergy in lymphocytes. J. Immunol. 177, 7559–7566 (2006).
Schwartz, M. Rho signalling at a glance. J. Cell Sci. 117, 5457–5458 (2004).
Perry, W. L. et al. The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a18H mice. Nature Genet. 18, 143–146 (1998).
Angers, A., Ramjaun, A. R. & McPherson, P. S. The HECT domain ligase itch ubiquitinates endophilin and localizes to the trans-Golgi network and endosomal system. J. Biol. Chem. 279, 11471–11479 (2004).
Mondino, A. et al. Defective transcription of the IL-2 gene is associated with impaired expression of c-Fos, FosB, and JunB in anergic T helper 1 cells. J. Immunol. 157, 2048–2057 (1996).
Fang, D. et al. Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation. Nature Immunol. 3, 281–287 (2002).
Gao, M. et al. Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch. Science 306, 271–275 (2004). This paper nicely shows how extracellular stimuli through the MAPK pathway regulate the turnover of the JUN family of transcription factors by ITCH.
Gallagher, E., Gao, M., Liu, Y. C. & Karin, M. Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change. Proc. Natl Acad. Sci. USA 103, 1717–1722 (2006).
Yang, C. et al. Negative regulation of the E3 ubiquitin ligase itch via Fyn-mediated tyrosine phosphorylation. Mol. Cell 21, 135–141 (2006).
Fang, D. & Kerppola, T. K. Ubiquitin-mediated fluorescence complementation reveals that Jun ubiquitinated by Itch/AIP4 is localized to lysosomes. Proc. Natl Acad. Sci. USA 101, 14782–14787 (2004).
Venuprasad, K. et al. Convergence of Itch-induced ubiquitination with MEKK1-JNK signaling in Th2 tolerance and airway inflammation. J. Clin. Invest. 116, 1117–1126 (2006).
Harvey, K. F., Shearwin-Whyatt, L. M., Fotia, A., Parton, R. G. & Kumar, S. N4WBP5, a potential target for ubiquitination by the Nedd4 family of proteins, is a novel Golgi-associated protein. J. Biol. Chem. 277, 9307–9317 (2002).
Oliver, P. M. et al. Ndfip1 protein promotes the function of itch ubiquitin ligase to prevent T cell activation and T helper 2 cell-mediated inflammation. Immunity 25, 929–940 (2006).
Cristillo, A. D., Nie, L., Macri, M. J. & Bierer, B. E. Cloning and characterization of N4WBP5A, an inducible, cyclosporine-sensitive, Nedd4-binding protein in human T lymphocytes. J. Biol. Chem. 278, 34587–34597 (2003).
Magnifico, A. et al. WW domain HECT E3s target Cbl RING finger E3s for proteasomal degradation. J. Biol. Chem. 278, 43169–43177 (2003).
Mouchantaf, R. et al. The ubiquitin ligase itch is auto-ubiquitylated in vivo and in vitro but is protected from degradation by interacting with the deubiquitylating enzyme FAM/USP9X. J. Biol. Chem. 281, 38738–38747 (2006).
Hicke, L., Schubert, H. L. & Hill, C. P. Ubiquitin-binding domains. Nature Rev. Mol. Cell Biol. 6, 610–621 (2005).
Carpino, N. et al. Regulation of ZAP-70 activation and TCR signaling by two related proteins, Sts-1 and Sts-2. Immunity 20, 37–46 (2004).
Kowanetz, K. et al. Suppressors of T-cell receptor signaling Sts-1 and Sts-2 bind to Cbl and inhibit endocytosis of receptor tyrosine kinases. J. Biol. Chem. 279, 32786–32795 (2004).
Feshchenko, E. A. et al. TULA: an SH3- and UBA-containing protein that binds to c-Cbl and ubiquitin. Oncogene 23, 4690–4706 (2004).
Pickart, C. M. Mechanisms underlying ubiquitination. Annu. Rev. Biochem. 70, 503–533 (2001).
Nijman, S. M. et al. A genomic and functional inventory of deubiquitinating enzymes. Cell 123, 773–786 (2005).
Cadwell, K. & Coscoy, L. Ubiquitination on nonlysine residues by a viral E3 ubiquitin ligase. Science 309, 127–130 (2005).
Cambier, J. C., Gauld, S. B. Merrell, K. T. & Vilen, B. J. B-cell anergy: from transgenic models to naturally occurring anergic B cells? Nature Rev. Immunol. 7, 633–643 (2007)
Acknowledgements
We apologize to all those researchers who have made contributions to the field of T-cell tolerance and anergy but were not discussed due to space restrictions. We thank L. Su and the editors for discussions and critical reading of the manuscript. Supported by the National Institutes of Health, USA, grants CA65237 and DK078123.
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Glossary
- Central tolerance
-
The lack of self-responsiveness that occurs during lymphocyte development in the central lymphoid organs. B-cell progenitors in the bone marrow and T-cell progenitors in the thymus that strongly recognize self antigen either undergo further rearrangement of antigen-receptor genes to avoid reactivity to self or face deletion by apoptosis.
- Peripheral tolerance
-
The lack of self-responsiveness of mature lymphocytes in the periphery to specific antigens. These mechanisms can control potentially self-reactive lymphocytes that have escaped central tolerance or prevent immune responses to specialized self proteins that were not present during establishment of central tolerance. Peripheral tolerance is associated with suppression of self-reactive antibody production by B cells and inhibition of self-reactive effector cells, such as cytotoxic T lymphocytes.
- E3 ubiquitin ligase
-
An enzyme that attaches ubiquitin to substrate proteins. Single subunit E3 ubiquitin ligases contain both the substrate-binding domain(s) and E2-tranferase recruitment machinery in the same polypeptide chain, whereas multisubunit E3 ubiquitin ligases divide these functions between individual protein components. E3 ubiquitin ligases are further classified on the basis of their E2-transferase recruitment domains: HECT-type, RING-finger-type and U-box-type.
- Adaptive tolerance
-
Also known as in vivo anergy, this phenomenon results from the challenge of T cells in the periphery by either superantigen or specific peptides that results in T-cell activation in the absence of upregulated co-stimulation on antigen-presenting cells. This state differs from in vitro clonal T-cell anergy in many ways, most notably in its requirement for persistent antigen presentation to maintain the anergic state.
- Activator protein 1
-
(AP1). A transcription factor heterodimer of FOS and JUN that is formed following T-cell activation and is critically important for inducing the transcription of interleukin-2.
- Cyclosporin A
-
An immunosuppressive drug that inhibits calcineurin, a Ca2+-dependent serine/threonine phosphatase necessary for the nuclear translocation of the transcription factor NFAT (nuclear factor of activated T cells).
- Guanine-nucleotide-exchange factor
-
(GEF). A protein that stimulates the exchange of guanine diphosphate (GDP) for guanine triphosphate (GTP) on small GTPases, resulting in activation of the GTPase.
- Heterokaryon
-
Any cell with more than one nucleus and the nuclei of which are not all of the same genetic constitution. The term heterokaryon can also refer to a tissue composed of such cells.
- Superantigen
-
A microbial protein that activates all T cells expressing a particular set of T-cell receptor (TCR) Vβ chains by crosslinking the TCR to a particular MHC regardless of the peptide presented.
- Immunological synapse
-
A region that can form between two cells of the immune system in close contact. The immunological synapse originally referred to the interaction between a T cell and an antigen-presenting cell. It involves adhesion molecules, as well as antigen receptors and cytokine receptors.
- Small interfering RNA
-
(siRNA). Synthetic RNA molecules of 19–23 nucleotides that are used to 'knockdown' (that is, silence the expression of) a specific gene. This is known as RNA interference (RNAi) and is mediated by the sequence-specific degradation of mRNA.
- Detergent-resistant microdomains
-
(DRMs). Cell-membrane extracts that are enriched in cholesterol, phospholipids and sphingolipids, which are liquid ordered yet insoluble in non-ionic detergents. They are often referred to as lipid rafts, which provide ordered structure to the lipid bilayer and have the ability to include or exclude specific signalling molecules and complexes.
- Ubiquitin-binding proteins
-
Proteins that contain one of the structurally diverse domains that can directly bind (generally with weak to moderate affinity) to ubiquitin attached to substrates. These domains include the ubiquitin-interacting motif (UIM), the ubiquitin associated (UBA) domain and the ubiquitin-conjugating enzyme variant (UEV) domain.
- Ionomycin
-
A calcium ionophore from Streptomyces conglobatus that induces the release of intracellular calcium stores.
- OTU domain
-
(Ovarian tumour domain). A domain that is found in a large family of proteins characterized by the presence of a putative catalytic triad of cysteine proteases. Several of these proteins are known to function as deubiquitylating or ubiquitin-modifying enzymes.
- Agouti locus
-
The agouti locus on mouse chromosome 2 determines the coat colour of a mouse by regulating the synthesis of yellow pigment by hair melanocytes. Mutations in this locus are also linked to immunological defects and the development of obesity and neoplasms.
- C2 domain
-
A versatile interaction domain that binds a wide variety of substrates including various lipids, calcium ions and phosphotyrosine residues.
- WW domain
-
A protein–protein interaction module that contains two conserved tryptophan (W) residues that are 20–22 amino acids apart and that interacts with proline-rich motifs.
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Fathman, C., Lineberry, N. Molecular mechanisms of CD4+ T-cell anergy. Nat Rev Immunol 7, 599–609 (2007). https://doi.org/10.1038/nri2131
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DOI: https://doi.org/10.1038/nri2131
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