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  • Review Article
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CD28-mediated co-stimulation: a quantitative support for TCR signalling

Key Points

  • CD28 potently enhances T-cell receptor (TCR)-induced proliferation and differentiation of naive T cells, especially at low TCR occupancy, making it responsible for the signal two predicted by the two-signal hypothesis of lymphocyte activation.

  • CD28 is a homodimer expressed by most mouse T cells, 90% of human CD4+ T cells and 50% of human CD8+ T cells. CD28 interacts with the two structurally homologous ligands — B7.1 (CD80) and B7.2 (CD86), expressed by activated antigen-presenting cells (APCs), such as dendritic cells.

  • CD28-deficient mice have reduced responses to infectious pathogens, allograft antigens, graft-versus-host disease, contact hypersensitivity and asthma.

  • Ligation of CD28 accelerates cell-cycle progression by enhancing the expression of D-cyclins, the activation of cyclin-dependent kinases and phosphorylation of the retinoblastoma family of proteins. CD28 favours T-cell survival by inducing nuclear factor-κB (NF-κB)-dependent expression of the anti-apoptotic protein BCL-XL and the development of T helper 2 (TH2) cells by promoting the expression of a 'second wave' of co-stimulatory receptors (such as CD40 ligand, OX40 and inducible co-stimulatory molecule (ICOS)

  • Ligation of CD28 triggers the activation of the SRC-family protein tyrosine kinases (PTKs) LCK and FYN, phosphatidylinositide-3-kinase, the guanosine exchange factor VAV1 and TEC PTKs.

  • CD28 amplifies membrane-proximal signalling that is generated by TCR ligation. TCR stimulation generates the central scaffolding (that is, the adaptors linker for activated T cells (LAT) and SH2-domain-containing leukocyte protein of 76 kDa (SLP76) on which CD28-activated signalling elements might dock for sustaining activation. One effect of CD28 co-stimulation is to reinforce actin-cytoskeleton rearrangement, which drives lipid-raft coalescence, TCR clustering and integrin activation.

  • A support to a quantitative view of co-stimulation comes from microarray analysis showing that TCR-induced expression of many genes in primary T cells is amplified (or suppressed) to varying degrees by CD28 co-stimulation but no new gene is induced by CD28 co-ligation.

Abstract

The ability of naive T cells to clonally expand and acquire effector functions depends on the strength of signals received by the T-cell receptor (TCR) and by an array of co-stimulatory receptors — the most prominent of which is CD28. In this review, we discuss recent genetic, biochemical and biophysical data that indicate a modified view of the molecular mechanism by which ligation of CD28 amplifies TCR-mediated T-cell activation. These studies indicate that the commonly held notion of a qualitative signalling role of CD28 in T-cell activation should be revised.

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Figure 1: Physiological and signalling roles of CD28 co-stimulation.
Figure 2: CD28-enhanced expression of a 'second wave' of co-stimulatory receptors.
Figure 3: Signalling tails of CD28 and TCR-associated CD3 chains.
Figure 4: CD28-activated VAV1 and its effects on cytoskeleton changes.
Figure 5: TCR–LAT and CD28 signalling pathways.
Figure 6: Qualitative and/or quantitative signalling features of CD28 co-stimulation.

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References

  1. Goodnow, C. C. Pathways for self-tolerance and the treatment of autoimmune diseases. Lancet 357, 2115–2121 (2001).

    CAS  PubMed  Google Scholar 

  2. Lafferty, K. J., Misko, I. S. & Cooley, M. A. Allogeneic stimulation modulates the in vitro response of T cells to transplantation antigen. Nature 249, 275–276 (1974).

    CAS  PubMed  Google Scholar 

  3. Sharpe, A. H. & Freeman, G. J. The B7–CD28 superfamily. Nature Rev. Immunol. 2, 116–126 (2002).

    CAS  Google Scholar 

  4. Lenschow, D. J., Walunas, T. L. & Bluestone, J. A. CD28/B7 system of T cell co-stimulation. Annu. Rev. Immunol. 14, 233–258 (1996).

    CAS  PubMed  Google Scholar 

  5. Shahinian, A. et al. Differential T cell co-stimulatory requirements in CD28-deficient mice. Science 261, 609–612 (1993). The first group to describe the CD28 knockout mouse, illustrating that some, but not all, immune responses are affected (see also reference 13).

    CAS  PubMed  Google Scholar 

  6. King, C. L., Xianli, J., June, C. H., Abe, R. & Lee, K. P. CD28-deficient mice generate an impaired TH2 response to Schistosoma mansoni infection. Eur. J. Immunol. 26, 2448–2455 (1996).

    CAS  PubMed  Google Scholar 

  7. Mittrucker, H. W., Kursar, M., Kohler, A., Hurwitz, R. & Kaufmann, S. H. Role of CD28 for the generation and expansion of antigen-specific CD8+ T lymphocytes during infection with Listeria monocytogenes. J. Immunol. 167, 5620–5627 (2001).

    CAS  PubMed  Google Scholar 

  8. Compton, H. L. & Farrell, J. P. CD28 co-stimulation and parasite dose combine to influence the susceptibility of BALB/c mice to infection with Leishmania major. J. Immunol. 168, 1302–1308 (2002).

    CAS  PubMed  Google Scholar 

  9. Salomon, B. & Bluestone, J. A. Complexities of CD28/B7: CTLA-4 co-stimulatory pathways in autoimmunity and transplantation. Annu. Rev. Immunol. 19, 225–252 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Via, C. S., Rus, V., Nguyen, P., Linsley, P. & Gause, W. C. Differential effect of CTLA4Ig on murine graft-versus-host disease (GVHD) development: CTLA4Ig prevents both acute and chronic GVHD development but reverses only chronic GVHD. J. Immunol. 157, 4258–4267 (1996).

    CAS  PubMed  Google Scholar 

  11. Kondo, S., Kooshesh, F., Wang, B., Fujisawa, H. & Sauder, D. N. Contribution of the CD28 molecule to allergic and irritant-induced skin reactions in CD28−/− mice. J. Immunol. 157, 4822–4829 (1996).

    CAS  PubMed  Google Scholar 

  12. Krinzman, S. J. et al. Inhibition of T cell co-stimulation abrogates airway hyperresponsiveness in a murine model. J. Clin. Invest. 98, 2693–2699 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Green, J. M. et al. Absence of B7-dependent responses in CD28-deficient mice. Immunity 1, 501–508 (1994).

    CAS  PubMed  Google Scholar 

  14. Lucas, P. J., Negishi, I., Nakayama, K., Fields, L. E. & Loh, D. Y. Naive CD28-deficient T cells can initiate but not sustain an in vitro antigen-specific immune response. J. Immunol. 154, 5757–5768 (1995).

    CAS  PubMed  Google Scholar 

  15. Gudmundsdottir, H., Wells, A. D. & Turka, L. A. Dynamics and requirements of T cell clonal expansion in vivo at the single-cell level: effector function is linked to proliferative capacity. J. Immunol. 162, 5212–5223 (1999).

    CAS  PubMed  Google Scholar 

  16. Lane, P. et al. B cell function in mice transgenic for mCTLA4-H γ1: lack of germinal centers correlated with poor affinity maturation and class switching despite normal priming of CD4+ T cells. J. Exp. Med. 179, 819–830 (1994).

    CAS  PubMed  Google Scholar 

  17. Ferguson, S. E., Han, S., Kelsoe, G. & Thompson, C. B. CD28 is required for germinal center formation. J. Immunol. 156, 4576–4581 (1996).

    CAS  PubMed  Google Scholar 

  18. Rulifson, I. C., Sperling, A. I., Fields, P. E., Fitch, F. W. & Bluestone, J. A. CD28 co-stimulation promotes the production of TH2 cytokines. J. Immunol. 158, 658–665 (1997).

    CAS  PubMed  Google Scholar 

  19. Schweitzer, A. N., Borriello, F., Wong, R. C., Abbas, A. K. & Sharpe, A. H. Role of co-stimulators in T cell differentiation: studies using antigen-presenting cells lacking expression of CD80 or CD86. J. Immunol. 158, 2713–2722 (1997).

    CAS  PubMed  Google Scholar 

  20. Prilliman, K. R. et al. Cutting edge: a crucial role for B7-CD28 in transmitting T help from APC to CTL. J. Immunol. 169, 4094–4097 (2002).

    CAS  PubMed  Google Scholar 

  21. Borriello, F. et al. B7-1 and B7-2 have overlapping, critical roles in immunoglobulin class switching and germinal center formation. Immunity 6, 303–313 (1997).

    CAS  PubMed  Google Scholar 

  22. McAdam, A. J., Schweitzer, A. N. & Sharpe, A. H. The role of B7 co-stimulation in activation and differentiation of CD4+ and CD8+ T cells. Immunol. Rev. 165, 231–247 (1998).

    CAS  PubMed  Google Scholar 

  23. Kane, L. P., Lin, J. & Weiss, A. It's all Rel-ative: NF-κB and CD28 co-stimulation of T-cell activation. Trends Immunol. 23, 413–420 (2002). A review of co-stimulation on nuclear factor-κB (NF-κB) activation.

    CAS  PubMed  Google Scholar 

  24. Michel, F. et al. CD28 utilizes Vav-1 to enhance TCR-proximal signaling and NF-AT activation. J. Immunol. 165, 3820–3829 (2000).

    CAS  PubMed  Google Scholar 

  25. Diehn, M. et al. Genomic expression programs and the integration of the CD28 co-stimulatory signal in T cell activation. Proc. Natl Acad. Sci. USA 99, 11796–11801 (2002). A microarray study showing that CD28 augments the level of expression of genes targeted by T-cell receptor (TCR)-induced activation: a support to a quantitative view of co-stimulation (see also reference 62).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Rincon, M. & Flavell, R. AP-1 transcriptional activity requires both T-cell receptor-mediated and co-stimulatory signals in primary T lymphocytes. EMBO J. 13, 4370–4381 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Zuckerman, L. A., Pullen, L. & Miller, J. Functional consequences of co-stimulation by ICAM-1 on IL-2 gene expression and T cell activation. J. Immunol. 160, 3259–3268 (1998).

    CAS  PubMed  Google Scholar 

  28. Zhou, X. Y. et al. Molecular mechanisms underlying differential contribution of CD28 versus non-CD28 co-stimulatory molecules to IL-2 promoter activation. J. Immunol. 168, 3847–3854 (2002).

    CAS  PubMed  Google Scholar 

  29. Green, J. M., Karpitskiy, V., Kimzey, S. L. & Shaw, A. S. Coordinate regulation of T cell activation by CD2 and CD28. J. Immunol. 164, 3591–3595 (2000).

    CAS  PubMed  Google Scholar 

  30. Van Der Merwe, P. A. & Davis, S. J. Molecular interactions mediating T cell antigen recognition. Annu. Rev. Immunol. 21, 659–684 (2003). A review on the biophysical basis of immunoreceptor recognition.

    CAS  PubMed  Google Scholar 

  31. Shimaoka, M. et al. Structures of the αL I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation. Cell 112, 99–111 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Herold, K. C. et al. Regulation of C-C chemokine production by murine T cells by CD28/B7 co-stimulation. J. Immunol. 159, 4150–4153 (1997).

    CAS  PubMed  Google Scholar 

  33. Park, W. R. et al. CD28 co-stimulation is required not only to induce IL-12 receptor but also to render janus kinases/STAT4 responsive to IL-12 stimulation in TCR-triggered T cells. Eur. J. Immunol. 31, 1456–1464 (2001).

    CAS  PubMed  Google Scholar 

  34. 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).

    CAS  PubMed  Google Scholar 

  35. Reichert, P., Reinhardt, R. L., Ingulli, E. & Jenkins, M. K. Cutting edge: in vivo identification of TCR redistribution and polarized IL-2 production by naive CD4 T cells. J. Immunol. 166, 4278–4281 (2001).

    CAS  PubMed  Google Scholar 

  36. Bonnevier, J. L. & Mueller, D. L. Cutting Edge: B7/CD28 interactions regulate cell cycle progression independent of the strength of TCR signaling. J. Immunol. 169, 6659–6663 (2002).

    CAS  PubMed  Google Scholar 

  37. Kundig, T. M. et al. Immune responses in interleukin-2-deficient mice. Science 262, 1059–1061 (1993).

    CAS  PubMed  Google Scholar 

  38. Lantz, O., Grandjean, I., Matzinger, P. & Di Santo, J. P. γ chain required for naive CD4+ T cell survival but not for antigen proliferation. Nature Immunol. 1, 54–58 (2000).

    CAS  Google Scholar 

  39. Appleman, L. J., Berezovskaya, A., Grass, I. & Boussiotis, V. A. CD28 co-stimulation mediates T cell expansion via IL-2-independent and IL-2-dependent regulation of cell cycle progression. J. Immunol. 164, 144–151 (2000).

    CAS  PubMed  Google Scholar 

  40. Ho, A. & Dowdy, S. F. Regulation of G1 cell-cycle progression by oncogenes and tumor suppressor genes. Curr. Opin. Genet. Dev. 12, 47–52 (2002).

    CAS  PubMed  Google Scholar 

  41. Boonen, G. J. et al. CD28 induces cell cycle progression by IL-2-independent downregulation of p27kip1 expression in human peripheral T lymphocytes. Eur. J. Immunol. 29, 789–798 (1999).

    CAS  PubMed  Google Scholar 

  42. Kovalev, G. I., Franklin, D. S., Coffield, V. M., Xiong, Y. & Su, L. An important role of CDK inhibitor p18(INK4c) in modulating antigen receptor-mediated T cell proliferation. J. Immunol. 167, 3285–3292 (2001).

    CAS  PubMed  Google Scholar 

  43. Lea, N. C. et al. Commitment point during G0—>G1 that controls entry into the cell cycle. Mol. Cell Biol. 23, 2351–2361 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Sherr, C. J. & Roberts, J. M. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13, 1501–1512 (1999).

    CAS  PubMed  Google Scholar 

  45. Appleman, L. J., van Puijenbroek, A. A., Shu, K. M., Nadler, L. M. & Boussiotis, V. A. CD28 co-stimulation mediates downregulation of p27kip1 and cell cycle progression by activation of the PI3K/PKB signaling pathway in primary human T cells. J. Immunol. 168, 2729–2736 (2002).

    CAS  PubMed  Google Scholar 

  46. Polymenis, M. & Schmidt, E. V. Coordination of cell growth with cell division. Curr. Opin. Genet. Dev. 9, 76–80 (1999).

    CAS  PubMed  Google Scholar 

  47. Schmelzle, T. & Hall, M. N. TOR, a central controller of cell growth. Cell 103, 253–262 (2000).

    CAS  PubMed  Google Scholar 

  48. Sears, R. C. & Nevins, J. R. Signaling networks that link cell proliferation and cell fate. J. Biol. Chem. 277, 11617–11620 (2002).

    CAS  PubMed  Google Scholar 

  49. Perez, V. L. et al. Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement. Immunity 6, 411–417 (1997).

    CAS  PubMed  Google Scholar 

  50. Rathmell, J. C. & Thompson, C. B. Pathways of apoptosis in lymphocyte development, homeostasis, and disease. Cell 109, S97–S107 (2002).

    CAS  PubMed  Google Scholar 

  51. Gett, A. V., Sallusto, F., Lanzavecchia, A. & Geginat, J. T cell fitness determined by signal strength. Nature Immunol. 4, 355–360 (2003).

    CAS  Google Scholar 

  52. Noel, P. J., Boise, L. H., Green, J. M. & Thompson, C. B. CD28 co-stimulation prevents cell death during primary T cell activation. J. Immunol. 157, 636–642 (1996).

    CAS  PubMed  Google Scholar 

  53. Schwartz, R. H. T cell anergy. Annu. Rev. Immunol. 21, 305–334 (2003).

    CAS  PubMed  Google Scholar 

  54. Boise, L. H. et al. CD28 co-stimulation can promote T cell survival by enhancing the expression of Bcl-XL . Immunity 3, 87–98 (1995).

    CAS  PubMed  Google Scholar 

  55. Khoshnan, A. et al. The NF-κB cascade is important in Bcl-xL expression and for the anti-apoptotic effects of the CD28 receptor in primary human CD4+ lymphocytes. J. Immunol. 165, 1743–1754 (2000).

    CAS  PubMed  Google Scholar 

  56. Wan, Y. Y. & DeGregori, J. The survival of antigen-stimulated T cells requires NF-κB-mediated inhibition of p73 expression. Immunity 18, 331–342 (2003).

    CAS  PubMed  Google Scholar 

  57. Murphy, K. M. & Reiner, S. L. The lineage decisions of helper T cells. Nature Rev. Immunol. 2, 933–944 (2002).

    CAS  Google Scholar 

  58. Lanzavecchia, A. & Sallusto, F. Progressive differentiation and selection of the fittest in the immune response. Nature Rev. Immunol. 2, 982–987 (2002).

    CAS  Google Scholar 

  59. Grogan, J. L. et al. Early transcription and silencing of cytokine genes underlie polarization of T helper cell subsets. Immunity 14, 205–215 (2001).

    CAS  PubMed  Google Scholar 

  60. Ben-Sasson, S. Z., Gerstel, R., Hu-Li, J. & Paul, W. E. Cell division is not a 'clock' measuring acquisition of competence to produce IFN-γ or IL-4. J. Immunol. 166, 112–120 (2001).

    CAS  PubMed  Google Scholar 

  61. Das, J. et al. A critical role for NF-κB in GATA3 expression and TH2 differentiation in allergic airway inflammation. Nature Immunol. 2, 45–50 (2001).

    CAS  Google Scholar 

  62. Riley, J. L. et al. Modulation of TCR-induced transcriptional profiles by ligation of CD28, ICOS, and CTLA-4 receptors. Proc. Natl Acad. Sci. USA 99, 11790–11795 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Oosterwegel, M. A. et al. The role of CTLA-4 in regulating TH2 differentiation. J. Immunol. 163, 2634–2639 (1999).

    CAS  PubMed  Google Scholar 

  64. Bour-Jordan, H. et al. CTLA-4 regulates the requirement for cytokine-induced signals in TH2 lineage commitment. Nature Immunol. 4, 182–188 (2003).

    CAS  Google Scholar 

  65. Zhao, K. et al. Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling. Cell 95, 625–636 (1998).

    CAS  PubMed  Google Scholar 

  66. Attema, J. L. et al. The human IL-2 gene promoter can assemble a positioned nucleosome that becomes remodeled upon T cell activation. J. Immunol. 169, 2466–2476 (2002).

    CAS  PubMed  Google Scholar 

  67. Grogan, J. L. & Locksley, R. M. T helper cell differentiation: on again, off again. Curr. Opin. Immunol. 14, 366–372 (2002).

    CAS  PubMed  Google Scholar 

  68. Rao, S., Gerondakis, S., Woltring, D. & Shannon, M. F. c-Rel is required for chromatin remodeling across the IL-2 gene promoter. J. Immunol. 170, 3724–3731 (2003).

    CAS  PubMed  Google Scholar 

  69. Bruniquel, D. & Schwartz, R. H. Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process. Nature Immunol. 4, 235–240 (2003) The authors provided the first evidence of stable demethylation of a TCR/CD28-targeted gene minutes after triggering.

    CAS  Google Scholar 

  70. Avni, O. et al. TH cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nature Immunol. 3, 643–651 (2002).

    CAS  Google Scholar 

  71. Acuto, O., Omata-Mise, S., Mangino, G. & Michel, F. Molecular modifiers of T cell antigen receptor triggering threshold: the mechanism of CD28 co-stimulatory receptor. Immunol. Rev. 192, 1–11 (2003).

    Google Scholar 

  72. Samelson, L. E. Signal transduction mediated by the T cell antigen receptor: the role of adapter proteins. Annu. Rev. Immunol. 20, 371–394 (2002).

    CAS  PubMed  Google Scholar 

  73. Ward, S. CD28: a signaling perspective. Biochem. J. 318, 361–377 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Montixi, C. et al. Engagement of T cell receptor triggers its recruitment to low-density detergent-insoluble membrane domains. EMBO J. 17, 5334–5348 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Irles, C. et al. CD45 ectodomain controls interaction with GEMs and Lck activity for optimal TCR signaling. Nature Immunol. 4, 189–197 (2003).

    CAS  Google Scholar 

  76. Michel, F., Attal-Bonnefoy, G., Mangino, G., Mise-Omata, S. & Acuto, O. CD28 as a molecular amplifier extending TCR ligation and signaling capabilities. Immunity 15, 935–945 (2001). This paper provides evidence that CD28 signalling amplifies a cyclosporin-dependent pathway by activating a TEC protein tyrosine kinase (PTK) with consequent activation of phospholipase C-γ1 (PLC-γ1) and increase in calcium concentration. It supports the view that co-stimulation directly augments TCR-signalling capability (see also reference 125).

    CAS  PubMed  Google Scholar 

  77. Dower, N. A. et al. RasGRP is essential for mouse thymocyte differentiation and TCR signaling. Nature Immunol. 1, 317–321 (2000).

    CAS  Google Scholar 

  78. Ward, S. G. & Cantrell, D. A. Phosphoinositide 3-kinases in T lymphocyte activation. Curr. Opin. Immunol. 13, 332–338 (2001).

    CAS  PubMed  Google Scholar 

  79. Irvine, D. J., Purbhoo, M. A., Krogsgaard, M. & Davis, M. M. Direct observation of ligand recognition by T cells. Nature 419, 845–849 (2002).

    CAS  PubMed  Google Scholar 

  80. Rudd, C. E. Upstream-downstream: CD28 cosignal pathways and T cell function. Immunity 4, 527–534 (1996).

    CAS  PubMed  Google Scholar 

  81. Yang, W. C., Ghiotto, M., Barbarat, B. & Olive, D. The role of Tec protein-tyrosine kinase in T cell signaling. J. Biol. Chem. 274, 607–617 (1999).

    CAS  PubMed  Google Scholar 

  82. August, A. et al. CD28 is associated with and induces the immediate tyrosine phosphorylation and activation of the Tec family kinase ITK/EMT in the human Jurkat leukemic T-cell line. Proc. Natl Acad. Sci. USA 91, 9347–9351 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Klasen, D., Pages, F., Peyron, J. -F., Cantrell, D. A. & Olive, D. Two distinct regions of the CD28 intracytoplasmic domain are involved in the tyrosine phosphorylation of Vav and GTPase activating protein-associated p62 protein. Int. Immunol. 10, 481–489 (1998).

    CAS  PubMed  Google Scholar 

  84. Michel, F., Grimaud, L., Tuosto, L. & Acuto, O. Fyn and ZAP-70 are required for Vav phosphorylation in T cells stimulated by antigen-presenting cells. J. Biol. Chem. 273, 31932–31938 (1998).

    CAS  PubMed  Google Scholar 

  85. Parry, R. V. et al. Ligation of the T cell co-stimulatory receptor CD28 activates the serine-threonine protein kinase protein kinase B. Eur. J. Immunol. 27, 2495–2501 (1997).

    CAS  PubMed  Google Scholar 

  86. Cantrell, D. Protein kinase B (Akt) regulation and function in T lymphocytes. Semin. Immunol. 14, 19–26 (2002).

    CAS  PubMed  Google Scholar 

  87. Okkenhaug, K. et al. A point mutation in CD28 distinguishes proliferative signals from survival signals. Nature Immunol. 2, 325–332 (2001).

    CAS  Google Scholar 

  88. Burr, J. S. et al. Cutting edge: distinct motifs within CD28 regulate T cell proliferation and induction of Bcl-XL . J. Immunol. 166, 5331–5335 (2001).

    CAS  PubMed  Google Scholar 

  89. Harada, Y. et al. Critical requirement for the membrane-proximal cytosolic tyrosine residue for CD28-mediated co-stimulation in vivo. J. Immunol. 166, 3797–3803 (2001).

    CAS  PubMed  Google Scholar 

  90. Coudronniere, N., Villalba, M., Englund, N. & Altman, A. NF-κB activation induced by T cell receptor/CD28 co-stimulation is mediated by protein kinase C-θ. Proc. Natl Acad. Sci. USA 97, 3394–3399 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Kane, L. P., Andres, P. G., Howland, K. C., Abbas, A. K. & Weiss, A. Akt provides the CD28 co-stimulatory signal for upregulation of IL-2 and IFN-γ but not TH2 cytokines. Nature Immunol. 2, 37–44 (2001).

    CAS  Google Scholar 

  92. Beals, C. R., Sheridan, C. M., Turck, C. W., Gardner, P. & Crabtree, G. R. Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science 275, 1930–1934 (1997).

    CAS  PubMed  Google Scholar 

  93. Frauwirth, K. A. et al. The CD28 signaling pathway regulates glucose metabolism. Immunity 16, 769–777 (2002).

    CAS  PubMed  Google Scholar 

  94. Takesono, A., Finkelstein, L. D. & Schwartzberg, P. L. Beyond calcium: new signaling pathways for Tec family kinases. J. Cell Sci. 115, 3039–3048 (2002).

    CAS  PubMed  Google Scholar 

  95. Reynolds, L. F. et al. Vav1 transduces T cell receptor signals to the activation of phospholipase C-γ1 via phosphoinositide 3-kinase-dependent and-independent pathways. J. Exp. Med. 195, 1103–1114 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Wulfing, C. & Davis, M. M. A receptor/cytoskeletal movement triggered by co-stimulation during T cell activation. Science 282, 2266–2269 (1998).

    CAS  PubMed  Google Scholar 

  97. Nunès, J. A., Collette, Y., Truneh, A., Olive, D. & Cantrell, D. A. The role of p21ras in CD28 signal transduction: triggering of CD28 with antibodies, but not the ligand B7-1, activates p21ras. J. Exp. Med. 180, 1067–1076 (1994).

    PubMed  Google Scholar 

  98. Rengarajan, J., Tang, B. & Glimcher, L. H. NFATc2 and NFATc3 regulate TH2 differentiation and modulate TCR-responsiveness of naive THcells. Nature Immunol. 3, 48–54 (2002).

    CAS  Google Scholar 

  99. Fowell, D. J. et al. Impaired NFATc translocation and failure of TH2 development in Itk-deficient CD4+ T cells. Immunity 11, 399–409 (1999).

    CAS  PubMed  Google Scholar 

  100. Yoshida, H. et al. The transcription factor NF-ATc1 regulates lymphocyte proliferation and TH2 cytokine production. Immunity 8, 115–124 (1998).

    CAS  PubMed  Google Scholar 

  101. Marinari, B. et al. Vav cooperates with CD28 to induce NF-κB activation via a pathway involving Rac-1 and mitogen-activated kinase kinase 1. Eur. J. Immunol. 32, 447–456 (2002).

    CAS  PubMed  Google Scholar 

  102. Hehner, S. P., Hofmann, T. G., Dienz, O., Droge, W. & Schmitz, M. L. Tyrosine-phosphorylated Vav1 as a point of integration for T-cell receptor- and CD28-mediated activation of JNK, p38, and interleukin-2 transcription. J. Biol. Chem. 275, 18160–18171 (2000).

    CAS  PubMed  Google Scholar 

  103. Crooks, M. E. et al. CD28-mediated co-stimulation in the absence of phosphatidylinositol 3-kinase association and activation. Mol. Cell Biol. 15, 6820–6828 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Kim, H. H., Tharayil, M. & Rudd, C. E. Growth factor receptor-bound protein 2 SH2/SH3 domain binding to CD28 and its role in co-signaling. J. Biol. Chem. 273, 296–301 (1998).

    CAS  PubMed  Google Scholar 

  105. Aghazadeh, B., Lowry, W. E., Huang, X. -Y. & Rosen, M. K. Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation. Cell 102, 625–633 (2000).

    CAS  PubMed  Google Scholar 

  106. Michel, F. & Acuto, O. CD28 co-stimulation: a source of Vav-1 for TCR signaling with the help of SLP-76? Sci. STKE 2002, PE35 ( 2002).

    PubMed  Google Scholar 

  107. Turner, M. & Billadeau, D. D. VAV proteins as signal integrators for multi-subunit immune-recognition receptors. Nature Rev. Immunol. 2, 476–486 (2002).

    CAS  Google Scholar 

  108. Nunès, J. A., Truneh, A., Olive, D. & Cantrell, D. A. Signal transduction by CD28 co-stimulatory receptor on T cells. J. Biol. Chem. 271, 1591–1598 (1996).

    PubMed  Google Scholar 

  109. Tuosto, L., Michel, F. & Acuto, O. p95vav associates with tyrosine-phosphorylated SLP-76 in antigen-stimulated T cells. J. Exp. Med. 184, 1161–1166 (1996).

    CAS  PubMed  Google Scholar 

  110. Myung, P. S. et al. Differential requirement for SLP-76 domains in T cell development and function. Immunity 15, 1011–1026 (2001).

    CAS  PubMed  Google Scholar 

  111. Penninger, J. M. & Crabtree, G. R. The actin cytoskeleton and lymphocyte activation. Cell 96, 9–12 (1999).

    CAS  PubMed  Google Scholar 

  112. Wulfing, C., Bauch, A., Crabtree, G. R. & Davis, M. M. The vav exchange factor is an essential regulator in actin-dependent receptor translocation to the lymphocyte-antigen-presenting cell interface. Proc. Natl Acad. Sci. USA 97, 10150–10155 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Krawczyk, C. et al. Vav1 controls integrin clustering and MHC/peptide-specific cell adhesion to antigen-presenting cells. Immunity 16, 331–343 (2002).

    CAS  PubMed  Google Scholar 

  114. Ardouin, L. et al. Vav1 transduces TCR signals required for LFA-1 function and cell polarization at the immunological synapse. Eur. J. Immunol. 33, 790–797 (2003).

    CAS  PubMed  Google Scholar 

  115. Manetz, T. S. et al. Vav1 regulates phospholipase Cγ activation and calcium responses in mast cells. Mol. Cell Biol. 21, 3763–3774 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Cantrell, D. A. Phosphoinositide 3-kinase signalling pathways. J. Cell. Sci. 114, 1439–1445 (2001).

    CAS  PubMed  Google Scholar 

  117. Raab, M., Pfister, S. & Rudd, C. E. CD28 signaling via VAV/SLP-76 adaptors: regulation of cytokine transcription independent of TCR ligation. Immunity 15, 921–933 (2001).

    CAS  PubMed  Google Scholar 

  118. Carey, M. The enhanceosome and transcriptional synergy. Cell 92, 5–8 (1998).

    CAS  PubMed  Google Scholar 

  119. June, C. H., Ledbetter, J. A., Gillespie, M. M., Lindsten, T. & Thompson, C. B. T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression. Mol. Cell. Biol. 7, 4472–4481 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Rooney, J. W., Sun, Y. L., Glimcher, L. H. & Hoey, T. Novel NFAT sites that mediate activation of the interleukin-2 promoter in response to T-cell receptor stimulation. Mol. Cell Biol. 15, 6299–6310 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Freedman, B. D., Liu, Q. H., Somersan, S., Kotlikoff, M. I. & Punt, J. A. Receptor avidity and co-stimulation specify the intracellular Ca2+ signaling pattern in CD4+CD8+ thymocytes. J. Exp. Med. 190, 943–952 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Su, B. et al. JNK is involved in signal integration during co-stimulation of T lymphocytes. Cell 77, 727–736 (1994).

    PubMed  Google Scholar 

  123. Rivas, F. V., O'Herrin, S. & Gajewski, T. F. CD28 is not required for c-Jun N-terminal kinase activation in T cells. J. Immunol. 167, 3123–3128 (2001).

    CAS  PubMed  Google Scholar 

  124. Miller, A. T. & Berg, L. J. New insights into the regulation and functions of Tec family tyrosine kinases in the immune system. Curr. Opin. Immunol. 14, 331–340 (2002).

    CAS  PubMed  Google Scholar 

  125. Tuosto, L. & Acuto, O. CD28 affects the earliest signaling events generated by TCR engagement. Eur. J. Immunol. 28, 2131–2142 (1998).

    CAS  PubMed  Google Scholar 

  126. Viola, A., Schroeder, S., Sakakibara, Y. & Lanzavecchia, A. T lymphocyte co-stimulation mediated by reorganization of membrane microdomains. Science 283, 680–682 (1999). This paper provides evidence for a role of co-stimulation in facilitating the clustering of glycolipid-enriched membrane microdomains (GEMs).

    CAS  PubMed  Google Scholar 

  127. Bromley, S. K. et al. The immunological synapse and CD28–CD80 interactions. Nature Immunol. 2, 1159–1166 (2001).

    CAS  Google Scholar 

  128. Holdorf, A. D. et al. Proline residues in CD28 and the Src homology (SH)3 domain of Lck are required for T cell co-stimulation. J. Exp. Med. 190, 375–384 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Herndon, T. M., Shan, X. C., Tsokos, G. C. & Wange, R. L. ZAP-70 and SLP-76 regulate protein kinase C-θ and NF-κB activation in response to engagement of CD3 and CD28. J. Immunol. 166, 5654–5664 (2001).

    CAS  PubMed  Google Scholar 

  130. Huang, J. et al. CD28 plays a critical role in the segregation of PKCθ within the immunologic synapse. Proc. Natl Acad. Sci. USA 99, 9369–9373 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Wetzel, S. A., McKeithan, T. W. & Parker, D. C. Live-cell dynamics and the role of co-stimulation in immunological synapse formation. J. Immunol. 169, 6092–6101 (2002).

    CAS  PubMed  Google Scholar 

  132. Wulfing, C. et al. Co-stimulation and endogenous MHC ligands contribute to T cell recognition. Nature Immunol. 3, 42–47 (2002). Using live immunofluorescence, this paper shows that CD28 contributes to TCR triggering by facilitating the accumulation of TCRs (including non-ligated TCRs) at the immune synapse (see also reference 131).

    CAS  Google Scholar 

  133. Harder, T. & Simons, K. Clusters of glycolipid and glycosylphosphatidylinositol-anchored proteins in lymphoid cells: accumulation of actin regulated by local tyrosine phosphorylation. Eur. J. Immunol. 29, 556–562 (1999).

    CAS  PubMed  Google Scholar 

  134. Freiberg, B. A. et al. Staging and resetting T cell activation in SMACs. Nature Immunol. 3, 911–917 (2002).

    CAS  Google Scholar 

  135. 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). This work illustrates the point that CD28 signalling decreases the duration of TCR stimulation in determining T-cell fate (see also reference 145).

    CAS  PubMed  Google Scholar 

  136. Holdorf, A. D., Lee, K. H., Burack, W. R., Allen, P. M. & Shaw, A. S. Regulation of Lck activity by CD4 and CD28 in the immunological synapse. Nature Immunol. 3, 259–264 (2002).

    CAS  Google Scholar 

  137. Jun, J. E. et al. Identifying the MAGUK protein Carma-1 as a central regulator of humoral immune responses and atopy by genome-wide mouse mutagenesis. Immunity 18, 751–762 (2003). This paper describes a point mutation in CARMA1, which is associated with lipid rafts after immunoreceptor triggering (see reference 138), that affects some but not all of the signalling pathways in which NF-κB is implicated: an example of qualitative differences in biological response with a minimum change in the behaviour of a single signalling component (see also reference 146).

    CAS  PubMed  Google Scholar 

  138. Gaide, O. et al. CARMA1 is a critical lipid raft-associated regulator of TCR-induced NF-κB activation. Nature Immunol. 3, 836–843 (2002)

    CAS  Google Scholar 

  139. Lewis, R. S. Calcium signaling mechanisms in T lymphocytes. Annu. Rev. Immunol. 19, 497–521 (2001).

    CAS  PubMed  Google Scholar 

  140. Viola, A. & Lanzavecchia, A. T cell activation determined by T cell receptor number and tunable thresholds. Science 273, 104–106 (1996). The first evidence that ligation of CD28 decreases the threshold number of ligated TCRs that are required for a given biological response.

    CAS  PubMed  Google Scholar 

  141. Manickasingham, S. P., Anderton, S. M., Burkhart, C. & Wraith, D. C. Qualitative and quantitative effects of CD28/B7-mediated co-stimulation on naive T cells in vitro. J. Immunol. 161, 3827–3835 (1998).

    CAS  PubMed  Google Scholar 

  142. Schweitzer, A. N. & Sharpe, A. H. Studies using antigen-presenting cells lacking expression of both B7-1 (CD80) and B7-2 (CD86) show distinct requirements for B7 molecules during priming versus restimulation of TH2 but not TH1 cytokine production. J. Immunol. 161, 2762–2771 (1998).

    CAS  PubMed  Google Scholar 

  143. Rogers, P. R. & Croft, M. CD28, Ox-40, LFA-1, and CD4 modulation of TH1/TH2 differentiation is directly dependent on the dose of antigen. J. Immunol. 164, 2955–2963 (2000).

    CAS  PubMed  Google Scholar 

  144. Deenick, E. K., Gett, A. V. & Hodgkin, P. D. Stochastic model of T cell proliferation: a calculus revealing IL-2 regulation of precursor frequencies, cell cycle time, and survival. J. Immunol. 170, 4963–4972 (2003).

    CAS  PubMed  Google Scholar 

  145. Kündig, T. M. et al. Duration of TCR stimulation determines co-stimulatory requirements of T cells. Immunity 5, 41–52 (1996). The first in vivo data that support a quantitative model of co-stimulation.

    PubMed  Google Scholar 

  146. Gong, Q. et al. Disruption of T cell signaling networks and development by Grb2 haploid insufficiency. Nature Immunol. 2, 29–36 (2001). An example of how sensitive certain biological responses are to a relatively small variation of a signalling component.

    CAS  Google Scholar 

  147. Arendt, C. W., Albrecht, B., Soos, T. J. & Littman, D. R. Protein kinase C-θ: signaling from the center of the T-cell synapse. Curr. Opin. Immunol. 14, 323–330 (2002).

    CAS  PubMed  Google Scholar 

  148. Villalba, M. et al. Translocation of PKCθ in T cells is mediated by a nonconventional, PI3-K- and Vav-dependent pathway, but does not absolutely require phospholipase C. J. Cell. Biol. 157, 253–263 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Koretzky, G. A. & Myung, P. S. Positive and negative regulation of T-cell activation by adaptor proteins. Nature Rev. Immunol. 1, 95–107 (2001).

    CAS  Google Scholar 

  150. Griffiths, E. K. & Penninger, J. M. Communication between the TCR and integrins: role of the molecular adapter ADAP/Fyb/Slap. Curr. Opin. Immunol. 14, 317–322 (2002).

    CAS  PubMed  Google Scholar 

  151. Wang, H. et al. SKAP-55 regulates integrin adhesion and formation of T cell–APC conjugates. Nature Immunol. 4, 366–374 (2003).

    CAS  Google Scholar 

  152. Heyeck, S. D., Wilcox, H. M., Bunnell, S. C. & Berg, L. J. Lck phosphorylates the activation loop tyrosine of the Itk kinase domain and activates Itk kinase activity. J. Biol. Chem. 272, 25401–25408 (1997).

    CAS  PubMed  Google Scholar 

  153. Yang, W. C., Ching, K. A., Tsoukas, C. D. & Berg, L. J. Tec kinase signaling in T cells is regulated by phosphatidylinositol 3-kinase and the Tec pleckstrin homology domain. J. Immunol. 166, 387–395 (2001).

    CAS  PubMed  Google Scholar 

  154. Krawczyk, C. et al. Cbl-b is a negative regulator of receptor clustering and raft aggregation in T cells. Immunity 13, 463–473 (2000).

    CAS  PubMed  Google Scholar 

  155. Chuang, E. et al. The CD28 and CTLA-4 receptors associate with the serine/threonine phosphatase PP2A. Immunity 13, 313–322 (2000).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank P. Schwartzberg, R. Sen, F. Shannon and members of the Molecular Immunology Unit for discussions and suggestions, and W. Houssin for secretarial assistance. We thank the Pasteur Institute, the Association pour la Recherche sur le Cancer and the Centre National de la Recherche Scientifique for continuous grant support. Due to space restrictions, we apologize if we have omitted to cite any references.

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Correspondence to Oreste Acuto.

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DATABASES

LocusLink

4-1BB

BCL-XL

CARMA1

CD2

CD28

CD40L

CD80

CD86

c-REL

CTLA4

GATA3

GSK3α

GSK3β

ICOS

INK4C

ITK

KIP1

LAT

LFA1

MTOR

NFAT

NF-κB

OX40

PDK1

PLC-γ1

SLP76

T-bet

VAV1

WASP

ZAP70

Glossary

TWO-SIGNAL HYPOTHESIS

The two-signal hypothesis was proposed as a mechanism to explain how lymphocyte stimulation by antigen induces an immune response or unresponsiveness. Briefly, the signal delivered by the antigen receptor alone could promote tolerance whereas development of an immune response requires a 'second signal' from a soluble or membrane-bound co-stimulatory factor.

IMMUNORECEPTOR TYROSINE-BASED ACTIVATION MOTIFS

(ITAMs). Structural motifs that contain tyrosine residues, found in the cytoplasmic tails of several signalling molecules. The tyrosine residue in the Tyr-Xaa-Xaa-Leu/Ile motif is a target for phosphorylation by SRC kinases and subsequent binding of SH2-domain-containing proteins such as ZAP70 and SYK.

GLYCOLIPID-ENRICHED MEMBRANE MICRODOMAINS

(GEMs). Cholesterol-rich dynamic microdomains or 'lipid rafts' that provide ordered structure to the lipid bilayer and have the ability to include or exclude specific signalling molecules and complexes. GEMs are thought to be an important site for signal transduction.

MICROTUBULE ORGANIZING CENTRE

(MTOC). Region in the cell, such as a centrosome or a basal body, from which microtubules grow.

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Acuto, O., Michel, F. CD28-mediated co-stimulation: a quantitative support for TCR signalling. Nat Rev Immunol 3, 939–951 (2003). https://doi.org/10.1038/nri1248

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