Key Points
-
Cytotoxic T lymphocyte antigen 4 (CTLA4) and its homologue CD28 are crucial T cell proteins associated with immune regulation. They share the same ligands, CD80 and CD86, which are present on antigen-presenting cells (APCs).
-
CTLA4-deficient mice suffer from fatal lymphoproliferative disease and die by 3–4 weeks of age, indicating that CTLA4 is an essential negative regulator of T cell responses. By contrast, CD28-deficient mice are immunocompromised.
-
CTLA4 is a highly endocytic receptor that undergoes both recycling to the plasma membrane and degradation in lysosomes. The cytoplasmic domain, which is required for these functions, is highly conserved in mammals.
-
CTLA4 is expressed by regulatory T (TReg) cells and activated conventional T cells. Evidence suggests that CTLA4 is important for TReg cell suppressive function in many settings.
-
The molecular mechanism of CTLA4 function is still undecided and a number of cell-intrinsic and cell-extrinsic mechanisms have been proposed.
-
In vivo studies using bone marrow chimeric mice indicate that CTLA4-deficient T cells are not dysregulated in the presence of wild-type T cells. This suggests that the main non-redundant function of CTLA4 in vivo is a cell-extrinsic one.
-
Emerging evidence suggests that one cell-extrinsic function of CTLA4 may be to downregulate CD80 and CD86 expression on APCs, thereby limiting the ability of APCs to stimulate T cells via CD28.
Abstract
The T cell protein cytotoxic T lymphocyte antigen 4 (CTLA4) was identified as a crucial negative regulator of the immune system over 15 years ago, but its mechanisms of action are still under debate. It has long been suggested that CTLA4 transmits an inhibitory signal to the cells that express it. However, not all the available data fit with a cell-intrinsic function for CTLA4, and other studies have suggested that CTLA4 functions in a T cell-extrinsic manner. Here, we discuss the data for and against the T cell-intrinsic and -extrinsic functions of CTLA4.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Walker, L. S. & Abbas, A. K. The enemy within: keeping self-reactive T cells at bay in the periphery. Nature Rev. Immunol. 2, 11–19 (2002).
Brunkow, M. E. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nature Genet. 27, 68–73 (2001).
Wahl, S. M., Orenstein, J. M. & Chen, W. TGF-β influences the life and death decisions of T lymphocytes. Cytokine Growth Factor Rev. 11, 71–79 (2000).
Fehervari, Z., Yamaguchi, T. & Sakaguchi, S. The dichotomous role of IL-2: tolerance versus immunity. Trends Immunol. 27, 109–111 (2006).
Tivol, E. A. et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3, 541–547 (1995).
Waterhouse, P. et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270, 985–988 (1995). References 5 and 6 were the first reports of the lethal lymphoproliferative syndrome that occurs in CTLA4-deficient mice, demonstrating the central role of this molecule in the regulation of T cell immune responses.
Chambers, C. A., Sullivan, T. J. & Allison, J. P. Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ cells. Immunity 7, 885–895 (1997). This report shows that depletion of CD4+ T cells prevents lymphocytic infiltration of peripheral tissues in CTLA4-deficient mice, illustrating the role of CTLA4 in CD4+ T cell function.
Leach, D. R., Krummel, M. F. & Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734–1736 (1996).
Peggs, K. S., Quezada, S. A., Korman, A. J. & Allison, J. P. Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. Curr. Opin. Immunol. 18, 206–213 (2006).
Ueda, H. et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423, 506–511 (2003).
Vijayakrishnan, L. et al. An autoimmune disease-associated CTLA-4 splice variant lacking the B7 binding domain signals negatively in T cells. Immunity 20, 563–575 (2004).
Gough, S. C., Walker, L. S. & Sansom, D. M. CTLA4 gene polymorphism and autoimmunity. Immunol. Rev. 204, 102–115 (2005).
Sansom, D. M. CD28, CTLA-4 and their ligands: who does what and to whom? Immunology 101, 169–177 (2000).
Sansom, D. M., Manzotti, C. N. & Zheng, Y. What's the difference between CD80 and CD86? Trends Immunol. 24, 313–318 (2003).
Sansom, D. M. & Walker, L. S. The role of CD28 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) in regulatory T-cell biology. Immunol. Rev. 212, 131–148 (2006).
Keir, M. E. & Sharpe, A. H. The B7/CD28 costimulatory family in autoimmunity. Immunol. Rev. 204, 128–143 (2005).
Linsley, P. S. et al. Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J. Exp. Med. 173, 721–730 (1991).
Thompson, C. et al. CD28 activation pathway regulates the production of multiple T cell-derived lymphokines/cytokines. Proc. Natl Acad. Sci. USA 86, 1333–1337 (1993).
Boise, L. H. et al. CD28 costimulation can promote T cell survival by enhancing expression of Bcl-XL . Immunity 3, 87–98 (1995).
McLeod, J. D. et al. Activation of human T cells with superantigen and CD28 confers resistance to apoptosis by CD95. J. Immunol. 160, 2072–2079 (1998).
Ferguson, S. E., Han, S., Kelsoe, G. & Thompson, C. B. CD28 is required for germinal center formation. J. Immunol. 156, 4576–4581 (1996).
Iezzi, G., Karjalainen, K. & Lanzavecchia, A. The duration of antigenic stimulation determines the fate of naive and effector T cells. Immunity 8, 89–95 (1998).
Gett, A. V. & Hodgkin, P. D. A cellular calculus for signal integration by T cells. Nature Immunol. 1, 239–244 (2000).
Shahinian, A. et al. Differential T cell costimulatory requirements in CD28-deficient mice. Science 261, 609–612 (1993).
Walker, L. S., Gulbranson-Judge, A., Flynn, S., Brocker, T. & Lane, P. J. Co-stimulation and selection for T-cell help for germinal centres: the role of CD28 and OX40. Immunol. Today 21, 333–337 (2000).
Walunas, T. L. et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1, 405–413 (1994).
Krummel, M. F. & Allison, J. P. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J. Exp. Med. 182, 459–465 (1995).
Kearney, E. R. et al. Antigen-dependent clonal expansion of a trace population of antigen-specific CD4+ T cells in vivo is dependent on CD28 costimulation and inhibited by CTLA-4. J. Immunol. 155, 1032–1036 (1995).
Hurwitz, A. A., Sullivan, T. J., Sobel, R. A. & Allison, J. P. Cytotoxic T lymphocyte antigen-4 (CTLA-4) limits the expansion of encephalitogenic T cells in experimental autoimmune encephalomyelitis (EAE)-resistant BALB/c mice. Proc. Natl Acad. Sci. USA 99, 3013–3017 (2002).
Collins, A. V. et al. The interaction properties of costimulatory molecules revisited. Immunity 17, 201–210 (2002).
Lenschow, D. J. et al. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg. Science 257, 789–792 (1992).
Linsley, P. S. et al. Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science 257, 792–795 (1992).
Tivol, E. A. et al. CTLA4Ig prevents lymphoproliferation and fatal multiorgan tissue destruction in CTLA-4-deficient mice. J. Immunol. 158, 5091–5094 (1997).
Mandelbrot, D. A., McAdam, A. J. & Sharpe, A. H. B7–1 or B7–2 is required to produce the lymphoproliferative phenotype in mice lacking cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). J. Exp. Med. 189, 435–440 (1999).
Tai, X., Van Laethem, F., Sharpe, A. H. & Singer, A. Induction of autoimmune disease in CTLA-4−/− mice depends on a specific CD28 motif that is required for in vivo costimulation. Proc. Natl Acad. Sci. USA 104, 13756–13761 (2007). This study identified the C-terminal proline residues of CD28 that are required to cause the lymphoproliferative syndrome associated with CTLA4 deficiency. This emphasizes that the central role of CTLA4 is to inhibit the CD28 pathway.
Linsley, P. S. et al. Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes. J. Exp. Med. 176, 1595–1604 (1992).
Metzler, B., Burkhart, C. & Wraith, D. C. Phenotypic analysis of CTLA-4 and CD28 expression during transient peptide-induced T cell activation in vivo. Int. Immunol. 11, 667–675 (1999).
Read, S., Malmstrom, V. & Powrie, F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+CD4+ regulatory cells that control intestinal inflammation. J. Exp. Med. 192, 295–302 (2000).
Takahashi, T. et al. Immunologic self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 192, 303–310 (2000). References 38 and 39 provided the first evidence for a role for CTLA4 in T Reg cell function.
Mead, K. I. et al. Exocytosis of CTLA-4 is dependent on phospholipase D and ADP ribosylation factor-1 and stimulated during activation of regulatory T cells. J. Immunol. 174, 4803–4811 (2005).
Manzotti, C. N. et al. Integration of CD28 and CTLA-4 function results in differential responses of T cells to CD80 and CD86. Eur. J. Immunol. 36, 1413–1422 (2006).
Linsley, P. S. et al. Intracellular trafficking of CTLA-4 and focal localisation towards sites of TCR engagement. Immunity 4, 535–543 (1996). This study shows that CTLA4 is an intracellular protein that is stimulated to traffic to TCR contact sites.
Shiratori, T. et al. Tyrosine phosphorylation controls internalization of CTLA-4 by regulating its interaction with clathrin-associated adaptor complex AP-2. Immunity 6, 583–589 (1997). This work demonstrates the association of CTLA4 with the clathrin-associated adaptor complex AP2, which underpins its endocytic behaviour.
Chuang, E. et al. Interaction of CTLA-4 with the clathrin-associated protein AP50 results in ligand-independent endocytosis that limits cell surface expression. J. Immunol. 159, 144–151 (1997).
Zhang, Y. & Allison, J. P. Interaction of CTLA-4 with AP-50, a clathrin-coated pit adaptor protein. Proc. Natl Acad. Sci. USA 94, 9273–9278 (1997).
Schneider, H. et al. Cytolytic T lymphocyte-associated antigen-4 and the TCRζ/CD3 complex, but not CD28, interact with clathrin adaptor complexes AP-1 and AP-2. J. Immunol. 163, 1868–1879 (1999).
Egen, J. G. & Allison, J. P. Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity 16, 23–35 (2002). This study shows that TCR stimulation causes accumulation of CTLA4 at the immune synapse.
Qureshi, O. S. et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332, 600–603 (2011).
Iida, T. et al. Regulation of cell surface expression of CTLA-4 by secretion of CTLA-4-containing lysosomes upon activation of CD4+ T cells. J. Immunol. 165, 5062–5068 (2000).
Wu, Y. et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 126, 375–387 (2006).
Gavin, M. A. et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445, 771–775 (2007).
Thornton, A. M. & Shevach, E. M. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 188, 287–296 (1998).
Tang, Q. et al. Distinct roles of CTLA-4 and TGF-β in CD4+CD25+ regulatory T cell function. Eur. J. Immunol. 34, 2996–3005 (2004).
Manzotti, C. N. et al. Inhibition of human T cell proliferation by CTLA-4 utilizes CD80 and requires CD25+ regulatory T cells. Eur. J. Immunol. 32, 2888–2896 (2002).
Zheng, Y. et al. Acquisition of suppressive function by activated human CD4+ CD25− T cells is associated with the expression of CTLA-4 not FoxP3. J. Immunol. 181, 1683–1691 (2008).
Kataoka, H. et al. CD25+CD4+ regulatory T cells exert in vitro suppressive activity independent of CTLA-4. Int. Immunol. 17, 421–427 (2005). This study demonstrates that suppression by wild-type T Reg cells is CTLA4 dependent, but that alternative mechanisms can allow CTLA4-deficient cells to suppress immune responses.
Quezada, S. A., Peggs, K. S., Curran, M. A. & Allison, J. P. CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J. Clin. Invest. 116, 1935–1945 (2006).
Kavanagh, B. et al. CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependant fashion. Blood 112, 1175–1183 (2008).
Schmidt, E. M. et al. CTLA-4 controls regulatory T cell peripheral homeostasis and is required for suppression of pancreatic islet autoimmunity. J. Immunol. 182, 274–282 (2009).
Verhagen, J. et al. Enhanced selection of FoxP3+ T-regulatory cells protects CTLA-4-deficient mice from CNS autoimmune disease. Proc. Natl Acad. Sci. USA 106, 3306–3311 (2009).
Wing, K. et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 322, 271–275 (2008).
Read, S. et al. Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo. J. Immunol. 177, 4376–4383 (2006).
Sojka, D. K., Hughson, A. & Fowell, D. J. CTLA-4 is required by CD4+CD25+ Treg to control CD4+ T-cell lymphopenia-induced proliferation. Eur. J. Immunol. 39, 1544–1551 (2009).
Kolar, P. et al. CTLA-4 (CD152) controls homeostasis and suppressive capacity of regulatory T cells in mice. Arthritis Rheum. 60, 123–132 (2009).
Ise, W. et al. CTLA-4 suppresses the pathogenicity of self antigen-specific T cells by cell-intrinsic and cell-extrinsic mechanisms. Nature Immunol. 11, 129–135 (2010).
Jain, N., Nguyen, H., Chambers, C. & Kang, J. Dual function of CTLA-4 in regulatory T cells and conventional T cells to prevent multiorgan autoimmunity. Proc. Natl Acad. Sci. USA 107, 1524–1528 (2010).
Rubtsov, Y. P. et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28, 546–558 (2008).
Tang, Q. & Bluestone, J. A. The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nature Immunol. 9, 239–244 (2008).
Vignali, D. A., Collison, L. W. & Workman, C. J. How regulatory T cells work. Nature Rev. Immunol. 8, 523–532 (2008).
Krummel, M. F. & Allison, J. P. CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. J. Exp. Med. 183, 2533–2540 (1996).
Walunas, T. L., Bakker, C. Y. & Bluestone, J. A. CTLA-4 ligation blocks CD28-dependent T cell activation. J. Exp. Med. 183, 2541–2550 (1996).
Chuang, E. et al. The CD28 and CTLA-4 receptors associate with the serine/threonine phosphatase PP2A. Immunity 13, 313–322 (2000).
Parry, R. V. et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol. Cell. Biol. 25, 9543–9553 (2005).
Marengere, L. E. et al. Regulation of T cell receptor signaling by tyrosine phosphatase SYP association with CTLA-4. Science 272, 1170–1173 (1996).
Lee, K. M. et al. Molecular basis of T cell inactivation by CTLA-4. Science 282, 2263–2266 (1998).
Martin, M., Schneider, H., Azouz, A. & Rudd, C. E. Cytotoxic T lymphocyte antigen 4 and CD28 modulate cell surface raft expression in their regulation of T cell function. J. Exp. Med. 194, 1675–1681 (2001).
Chikuma, S., Imboden, J. B. & Bluestone, J. A. Negative regulation of T cell receptor-lipid raft interaction by cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 197, 129–135 (2003).
Darlington, P. J. et al. Surface cytotoxic T lymphocyte-associated antigen 4 partitions within lipid rafts and relocates to the immunological synapse under conditions of inhibition of T cell activation. J. Exp. Med. 195, 1337–1347 (2002).
Chuang, E. et al. Regulation of cytotoxic T lymphocyte-associated molecule-4 by Src kinases. J. Immunol. 162, 1270–1277 (1999).
Hu, H., Rudd, C. E. & Schneider, H. Src kinases Fyn and Lck facilitate the accumulation of phosphorylated CTLA-4 and its association with PI-3 kinase in intracellular compartments of T-cells. Biochem. Biophys. Res. Commun. 288, 573–578 (2001).
Schneider, H., Schwartzberg, P. L. & Rudd, C. E. Resting lymphocyte kinase (Rlk/Txk) phosphorylates the YVKM motif and regulates PI 3-kinase binding to T-cell antigen CTLA-4. Biochem. Biophys. Res. Commun. 252, 14–19 (1998).
Schneider, H., Valk, E., Leung, R. & Rudd, C. E. CTLA-4 activation of phosphatidylinositol 3-kinase (PI 3-K) and protein kinase B (PKB/AKT) sustains T-cell anergy without cell death. PLoS ONE 3, e3842 (2008).
Schneider, H. et al. Cutting edge: CTLA-4 (CD152) differentially regulates mitogen-activated protein kinases (extracellular signal-regulated kinase and c-Jun N-terminal kinase) in CD4+ T cells from receptor/ligand-deficient mice. J. Immunol. 169, 3475–3479 (2002).
Schneider, H., Smith, X., Liu, H., Bismuth, G. & Rudd, C. E. CTLA-4 disrupts ZAP70 microcluster formation with reduced T cell/APC dwell times and calcium mobilization. Eur. J. Immunol. 38, 40–47 (2008).
Calvo, C. R., Amsen, D. & Kruisbeek, A. M. Cytotoxic T lymphocyte antigen 4 (CTLA-4) interferes with extracellular signal-regulated kinase (ERK) and Jun NH2-terminal kinase (JNK) activation, but does not affect phosphorylation of T cell receptor ζ and ZAP70. J. Exp. Med. 186, 1645–1653 (1997).
Stein, P. H., Fraser, J. D. & Weiss, A. The cytoplasmic domain of CD28 is both necessary and sufficient for costimulation of interleukin-2 secretion and association with phosphatidylinositol 3′-kinase. Mol. Cell. Biol. 14, 3392–3402 (1994).
Araki, M. et al. Genetic evidence that the differential expression of the ligand-independent isoform of CTLA-4 is the molecular basis of the Idd5.1 type 1 diabetes region in nonobese diabetic mice. J. Immunol. 183, 5146–5157 (2009).
Chikuma, S., Abbas, A. K. & Bluestone, J. A. B7-independent inhibition of T cells by CTLA-4. J. Immunol. 175, 177–181 (2005).
Choi, J. M. et al. Transduction of the cytoplasmic domain of CTLA-4 inhibits TcR-specific activation signals and prevents collagen-induced arthritis. Proc. Natl Acad. Sci. USA 105, 19875–19880 (2008).
Choi, J. M. et al. Intranasal delivery of the cytoplasmic domain of CTLA-4 using a novel protein transduction domain prevents allergic inflammation. Nature Med. 12, 574–579 (2006).
Jeffery, L. et al. 1,25-dihydroxyvitamin D3 and interleukin-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J. Immunol. 183, 5458–5467 (2009).
Bowlus, C. L. The role of iron in T cell development and autoimmunity. Autoimmun. Rev. 2, 73–78 (2003).
Thompson, C. B. & Allison, J. P. The emerging role of CTLA-4 as an immune attenuator. Immunity 7, 445–450 (1997).
Alegre, M.-L. et al. Regulation of surface and intracellular expression of CTLA-4 on mouse T cells. J. Immunol. 157, 4762–4770 (1996).
Carreno, B. M. et al. CTLA-4 (CD152) can inhibit T cell activation by two different mechanisms depending on its level of cell surface expression. J. Immunol. 165, 1352–1356 (2000).
Yokosuka, T. et al. Spatiotemporal basis of CTLA-4 costimulatory molecule-mediated negative regulation of T cell activation. Immunity 33, 326–339 (2010).
Masteller, E. L., Chuang, E., Mullen, A. C., Reiner, S. L. & Thompson, C. B. Structural analysis of CTLA-4 function in vivo. J. Immunol. 164, 5319–5327 (2000).
Schneider, H., Valk, E., da Rocha Dias, S., Wei, B. & Rudd, C. E. CTLA-4 up-regulation of lymphocyte function-associated antigen 1 adhesion and clustering as an alternate basis for coreceptor function. Proc. Natl Acad. Sci. USA 102, 12861–12866 (2005).
Onishi, Y., Fehervari, Z., Yamaguchi, T. & Sakaguchi, S. Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation. Proc. Natl Acad. Sci. USA 105, 10113–10118 (2008).
Schneider, H. et al. Reversal of the TCR stop signal by CTLA-4. Science 313, 1972–1975 (2006).
Downey, J., Smith, A., Schneider, H., Hogg, N. & Rudd, C. E. TCR/CD3 mediated stop-signal is decoupled in T-cells from Ctla4 deficient mice. Immunol. Lett. 115, 70–72 (2008).
Tang, Q. et al. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nature Immunol. 7, 83–92 (2006).
Fife, B. T. et al. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nature Immunol. 10, 1185–1192 (2009).
Bachmann, M. F., Kohler, G., Ecabert, B., Mak, T. W. & Kopf, M. Cutting edge: lymphoproliferative disease in the absence of CTLA-4 is not T cell autonomous. J. Immunol. 163, 1128–1131 (1999). This seminal paper showed for the first time that CTLA4-deficient cells are controlled by a cohort of CTLA4-sufficient cells in mixed bone marrow chimaeras. Despite its relative under-appreciation, this represents the most reproducible experimental approach in CTLA4 biology.
Homann, D. et al. Lack of intrinsic CTLA-4 expression has minimal effect on regulation of antiviral T-cell immunity. J. Virol. 80, 270–280 (2006). A careful and comprehensive study of the responses of CTLA4-deficient and CTLA4-sufficient T cells in mixed bone marrow chimaeras. The study examined T cell proliferation, effector function, repertoire selection, functional avidity and memory.
Chikuma, S. & Bluestone, J. A. Expression of CTLA-4 and FOXP3 in cis protects from lethal lymphoproliferative disease. Eur. J. Immunol. 37, 1285–1289 (2007).
Friedline, R. H. et al. CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance. J. Exp. Med. 206, 421–434 (2009).
Tivol, E. A. & Gorski, J. Re-establishing peripheral tolerance in the absence of CTLA-4: complementation by wild-type T cells points to an indirect role for CTLA-4. J. Immunol. 169, 1852–1858 (2002).
Bachmann, M. F. et al. Normal pathogen-specific immune responses mounted by CTLA-4-deficient T cells: a paradigm reconsidered. Eur. J. Immunol. 31, 450–458 (2001).
Bachmann, M. F. et al. Normal responsiveness of CTLA-4-deficient anti-viral cytotoxic T cells. J. Immunol. 160, 95–100 (1998).
Grohmann, U. et al. CTLA-4-Ig regulates tryptophan catabolism in vivo. Nature Immunol. 3, 1097–1101 (2002).
Fallarino, F. et al. Modulation of tryptophan catabolism by regulatory T cells. Nature Immunol. 4, 1206–1212 (2003).
Munn, D. H. et al. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J. Exp. Med. 189, 1363–1372 (1999).
Mellor, A. L. et al. Specific subsets of murine dendritic cells acquire potent T cell regulatory functions following CTLA4-mediated induction of indoleamine 2,3 dioxygenase. Int. Immunol. 16, 1391–1401 (2004).
Orabona, C. et al. CD28 induces immunostimulatory signals in dendritic cells via CD80 and CD86. Nature Immunol. 5, 1134–1142 (2004).
Munn, D. H., Sharma, M. D. & Mellor, A. L. Ligation of B7–1/B7–2 by human CD4+ T cells triggers indoleamine 2,3-dioxygenase activity in dendritic cells. J. Immunol. 172, 4100–4110 (2004).
Walker, L. S. et al. Compromised OX40 function in CD28-deficient mice is linked with failure to develop CXC chemokine receptor 5-positive CD4 cells and germinal centers. J. Exp. Med. 190, 1115–1122 (1999).
Manches, O. et al. HIV-activated human plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase-dependent mechanism. J. Clin. Invest. 118, 3431–3439 (2008).
Davis, P. M., Nadler, S. G., Stetsko, D. K. & Suchard, S. J. Abatacept modulates human dendritic cell-stimulated T-cell proliferation and effector function independent of IDO induction. Clin. Immunol. 126, 38–47 (2008).
Agaugue, S., Perrin-Cocon, L., Coutant, F., Andre, P. & Lotteau, V. 1-Methyl-tryptophan can interfere with TLR signaling in dendritic cells independently of IDO activity. J. Immunol. 177, 2061–2071 (2006).
Chen, W., Jin, W. & Wahl, S. M. Engagement of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) induces transforming growth factor β (TGF-β) production by murine CD4+ T cells. J. Exp. Med. 188, 1849–1857 (1998).
Oida, T., Xu, L., Weiner, H. L., Kitani, A. & Strober, W. TGF-β-mediated suppression by CD4+CD25+ T cells is facilitated by CTLA-4 signaling. J. Immunol. 177, 2331–2339 (2006).
Sullivan, T. J. et al. Lack of a role for transforming growth factor-β in cytotoxic T lymphocyte antigen-4-mediated inhibition of T cell activation. Proc. Natl Acad. Sci. USA 98, 2587–2592 (2001).
Green, E. A., Gorelik, L., McGregor, C. M., Tran, E. H. & Flavell, R. A. CD4+CD25+ T regulatory cells control anti-islet CD8+ T cells through TGF-β–TGF-β receptor interactions in type 1 diabetes. Proc. Natl Acad. Sci. USA 100, 10878–10883 (2003).
Fahlen, L. et al. T cells that cannot respond to TGF-β escape control by CD4+CD25+ regulatory T cells. J. Exp. Med. 201, 737–746 (2005).
Shull, M. M. et al. Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992).
Magistrelli, G. et al. A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells. Eur. J. Immunol. 29, 3596–3602 (1999).
Oaks, M. K. & Hallett, K. M. Cutting edge: a soluble form of CTLA-4 in patients with autoimmune thyroid disease. J. Immunol. 164, 5015–5018 (2000).
Toussirot, E. et al. Increased production of soluble CTLA-4 in patients with spondylarthropathies correlates with disease activity. Arthritis Res. Ther. 11, R101 (2009).
Purohit, S. et al. Lack of correlation between the levels of soluble cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and the CT-60 genotypes. J. Autoimmune Dis. 2, 8 (2005).
Mayans, S. et al. CT60 genotype does not affect CTLA-4 isoform expression despite association to T1D and AITD in northern Sweden. BMC Med. Genet. 8, 3 (2007).
Berry, A., Tector, M. & Oaks, M. K. Lack of association between sCTLA-4 levels in human plasma and common CTLA-4 polymorphisms. J. Negat. Results Biomed. 7, 8 (2008).
Tector, M., Khatri, B. O., Kozinski, K., Dennert, K. & Oaks, M. K. Biochemical analysis of CTLA-4 immunoreactive material from human blood. BMC Immunol. 10, 51 (2009).
Tadokoro, C. E. et al. Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo. J. Exp. Med. 203, 505–511 (2006).
Misra, N., Bayry, J., Lacroix-Desmazes, S., Kazatchkine, M. D. & Kaveri, S. V. Cutting edge: human CD4+CD25+ T cells restrain the maturation and antigen-presenting function of dendritic cells. J. Immunol. 172, 4676–4680 (2004).
Cederbom, L., Hall, H. & Ivars, F. CD4+CD25+ regulatory T cells down-regulate co-stimulatory molecules on antigen-presenting cells. Eur. J. Immunol. 30, 1538–1543 (2000).
Kastenmuller, W. et al. Regulatory T cells selectively control CD8+ T cell effector pool size via IL-2 restriction. J. Immunol. 187, 3186–3197 (2011).
Oderup, C., Cederbom, L., Makowska, A., Cilio, C. M. & Ivars, F. Cytotoxic T lymphocyte antigen-4-dependent down-modulation of costimulatory molecules on dendritic cells in CD4+ CD25+ regulatory T-cell-mediated suppression. Immunology 118, 240–249 (2006).
Schildknecht, A. et al. FoxP3+ regulatory T cells essentially contribute to peripheral CD8+ T-cell tolerance induced by steady-state dendritic cells. Proc. Natl Acad. Sci. USA 107, 199–203 (2010).
Serra, P. et al. CD40 ligation releases immature dendritic cells from the control of regulatory CD4+CD25+ T cells. Immunity 19, 877–889 (2003).
Kusakari, S. et al. Trans-endocytosis of CD47 and SHPS-1 and its role in regulation of the CD47–SHPS-1 system. J. Cell Sci. 121, 1213–1223 (2008).
Marston, D. J., Dickinson, S. & Nobes, C. D. Rac-dependent trans-endocytosis of ephrinBs regulates Eph–ephrin contact repulsion. Nature Cell Biol. 5, 879–888 (2003).
Cagan, R. L., Kramer, H., Hart, A. C. & Zipursky, S. L. The bride of sevenless and sevenless interaction: internalization of a transmembrane ligand. Cell 69, 393–399 (1992).
Davis, D. M. Intercellular transfer of cell-surface proteins is common and can affect many stages of an immune response. Nature Rev. Immunol. 7, 238–243 (2007).
Greenwald, R. J., Boussiotis, V. A., Lorsbach, R. B., Abbas, A. K. & Sharpe, A. H. CTLA-4 regulates induction of anergy in vivo. Immunity 14, 145–155 (2001).
Eggena, M. P. et al. Cooperative roles of CTLA-4 and regulatory T cells in tolerance to an islet cell antigen. J. Exp. Med. 199, 1725–1730 (2004).
Walker, L. S., Ausubel, L. J., Chodos, A., Bekarian, N. & Abbas, A. K. CTLA-4 differentially regulates T cell responses to endogenous tissue protein versus exogenous immunogen. J. Immunol. 169, 6202–6209 (2002).
Bernard, D. et al. Costimulatory receptors in a teleost fish: typical CD28, elusive CTLA4. J. Immunol. 176, 4191–4200 (2006).
Hansen, J. D. et al. The B7 family of immunoregulatory receptors: a comparative and evolutionary perspective. Mol. Immunol. 46, 457–472 (2009).
Chambers, C. A., Cado, D., Truong, T. & Allison, J. P. Thymocyte development is normal in CTLA-4-deficient mice. Proc. Natl Acad. Sci. USA 94, 9296–9301 (1997).
Tang, A. L. et al. CTLA4 expression is an indicator and regulator of steady-state CD4+ FoxP3+ T cell homeostasis. J. Immunol. 181, 1806–1813 (2008).
Salomon, B. et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12, 431–440 (2000).
Ikemizu, S. et al. Structure and dimerization of a soluble form of B7–1. Immunity 12, 51–60 (2000).
Catalfamo, M., Tai, X., Karpova, T., McNally, J. & Henkart, P. A. TcR-induced regulated secretion leads to surface expression of CTLA-4 in CD4+CD25+ T cells. Immunology 125, 70–79 (2008).
Rudd, C. E. The reverse stop-signal model for CTLA4 function. Nature Rev. Immunol. 8, 153–160 (2008).
Acknowledgements
We are grateful to S. Sakaguchi and members of the Walker and Sansom groups for helpful discussions.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
Glossary
- Peripheral tolerance
-
The generation of tolerance to self for mature T cells that have left the thymus and are recirculating in the periphery.
- Regulatory T cells
-
(TReg cells). Cells that can suppress the activity of other T cells, including autoreactive T cells. Depletion of TReg cells results in the loss of peripheral tolerance and the development of autoimmune disease.
- Clathrin-coated pits
-
Membrane invaginations that contain transmembrane proteins and a layer of electron-dense clathrin, clathrin adaptors and other proteins on their cytoplasmic faces. These structures bud from the membrane to become clathrin-coated transport vesicles.
- Lipid rafts
-
Structures that are proposed to arise from phase separation of different plasma membrane lipids as a result of the selective coalescence of certain lipids on the basis of their physical properties. This results in the formation of distinct and stable lipid domains in membranes that might provide a platform for membrane-associated protein organization.
- Non-obese diabetic mice
-
(NOD mice). An inbred strain of mice that spontaneously develops T cell-mediated autoimmune diabetes. The Idd5 locus is one region that alters disease susceptibility in this mouse strain.
- Central supramolecular activation cluster
-
(cSMAC). During T cell activation, T cell receptors accumulate into a central cluster (known as the cSMAC) at the interface between the T cell and the antigen-presenting cell. The cSMAC is surrounded by a ring of LFA1 (known as the pSMAC), and this characteristic receptor organization (the cSMAC surrounded by the pSMAC) constitutes the mature immunological synapse.
- Tetramer staining
-
Biotinylated monomeric MHC molecules are folded in vitro together with a specific peptide that binds in the binding groove. These peptide–MHC complexes are then tetramerized using a fluorescently labelled streptavidin molecule. The tetramers bind T cells that express T cell receptors specific for the cognate peptide–MHC complex. They can therefore be used to track antigen-specific T cells by flow cytometry.
- Trans-endocytosis
-
The process by which a tightly associated receptor–ligand complex induces invagination of the plasma membrane and internalization of the complex into the receptor-bearing cell to form a membrane-limited transport vesicle.
- RAG
-
(Recombination activating gene). Rag1 and Rag2 are expressed in developing lymphocytes. Mice that are deficient for either of these genes fail to produce B and T cells owing to a developmental block in the gene rearrangement that is necessary for receptor expression.
Rights and permissions
About this article
Cite this article
Walker, L., Sansom, D. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat Rev Immunol 11, 852–863 (2011). https://doi.org/10.1038/nri3108
Published:
Issue Date:
DOI: https://doi.org/10.1038/nri3108
This article is cited by
-
Association between Cytotoxic T-Lymphocyte-Associated Antigen 4 (CTLA-4) Locus and Early-Onset Anti-acetylcholine Receptor-Positive Myasthenia Gravis in Serbian Patients
Molecular Neurobiology (2024)
-
CD4+CCR8+ Tregs in ovarian cancer: a potential effector Tregs for immune regulation
Journal of Translational Medicine (2023)
-
Liver metastasis from colorectal cancer: pathogenetic development, immune landscape of the tumour microenvironment and therapeutic approaches
Journal of Experimental & Clinical Cancer Research (2023)
-
Molecular and functional imaging in cancer-targeted therapy: current applications and future directions
Signal Transduction and Targeted Therapy (2023)
-
Identification of hub genes and immune infiltration in ulcerative colitis using bioinformatics
Scientific Reports (2023)
