Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The expanding B7 superfamily: Increasing complexity in costimulatory signals regulating T cell function

Nature Immunology volume 2, pages 203–209 (2001)Cite this article

Abstract

Upon encounter with specific antigen, naïve T helper precursor (THP) cells become activated. This event is regulated not only by engagement of the T cell receptor (TCR) with peptide presented in the context of major histocompatibility complex (MHC) class II molecules but by a number of costimulatory signals. CD28 engagement by B7-1 and B7-2 on resting THP cells provides a critical signal for initial cell cycle progression, interleukin 2 production and clonal expansion. However, largely as a consequence of the unraveling of the human genome, it is becoming clear that B7-1 and B7-2 are part of a larger family of related counter-receptors that play an essential role in regulating the fate of primed, rather then resting, THP cells. These molecules play an important sequential role and act, together with B7-1– and B7-2–primed T cells, in the acquisition of effector function and/or tolerance induction.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Phylogenetic alignmeny of human and mouse B7 family members.
Figure 2: Relative expression of B7 molecules in the immune system.
Figure 3: Distinct functions of B7 family members.
Figure 4: Complementary roles of B7-1 and B7-2 with B7RP-1 to regulate TH2 differentiation.
Figure 5: Coordinated role of the extended B7 family in the regulation of the immune response.

Similar content being viewed by others

References

  1. Bretscher, P. A. & Cohn, M. A theory of self and non self discrimination. Science, 169, 1042–1049 (1970).

    Article  CAS  Google Scholar 

  2. Lafferty, J. & Woolnough, J. A. The origin and mechanism of the allograft reaction. Immunol. Rev. 35 231–249 (1977).

    Article  CAS  Google Scholar 

  3. Schwartz, R. H. A cell culture model for T lymphocyte clonal anergy. Science 4961, 1349–1356 (1990).

    Article  Google Scholar 

  4. Garside, P. et al. Visualization of specific B and T lymphocyte interactions in the lymph node. Science 281, 96–99 (1998).

    Article  CAS  Google Scholar 

  5. Klaus, G. G. B., Humphret, J. H., Kunkl, A. & Dongworth, D. W. The follicular dendritic cell: its role in antigen presentation in the generation of immunological memory. Immunol. Rev. 53, 3–28 (1980).

    Article  CAS  Google Scholar 

  6. Aruffo, A. & Seed, B. Molecular cloning of a CD28 cDNA by a high-efficiency COS cell expression system. Proc. Natl Acad. Sci. USA 84, 8573–8577 (1987).

    Article  CAS  Google Scholar 

  7. 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. 12, 4472–4481. (1987)

    Article  Google Scholar 

  8. Harding, F. A., McArthur, J. G., Gross, J. A., Raulet, D. H. & Allison, J. P. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature 6370, 607–609 (1992).

    Article  Google Scholar 

  9. Jenkins, M. K., Taylor, P. S., Norton, S. D. & Urdahl, K. B. CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells. J. Immunol. 8, 2461–2466 (1991).

    Google Scholar 

  10. 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. (1997)

    Google Scholar 

  11. Shahinian, A. et al. Differential T cell costimulatory requirements in CD28-deficient mice. Science 261 609–612 (1993).

    Article  CAS  Google Scholar 

  12. Tada, Y. et al. CD28-deficient mice are highly resistant to collagen-induced arthritis. J. Immunol. 162, 203–208 (1999).

    CAS  PubMed  Google Scholar 

  13. Girvin, A. M. et al. A critical role for B7/CD28 costimulation in experimental autoimmune encephalomyelitis: a comparative study using costimulatory molecule-deficient mice and monoclonal antibody blockade. J. Immunol. 164, 136–143 (2000).

    Article  CAS  Google Scholar 

  14. Mathur, M. et al. CD28 interactions with either CD80 or CD86 are sufficient to induce allergic airway inflammation in mice. Am. J. Respir. Cell Mol. Biol. 21, 498–509 (1999).

    Article  CAS  Google Scholar 

  15. Brunet J. F. et al. A new member of the immunoglobulin superfamily CTLA-4. Nature 328, 267–270 (1987).

    Article  CAS  Google Scholar 

  16. Walunas, T. L. et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1, 405–413 (1994).

    Article  CAS  Google Scholar 

  17. 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).

    Article  CAS  Google Scholar 

  18. Leach, D. R., Krummel, M. F. & Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734–1736 (1996).

    Article  CAS  Google Scholar 

  19. Luhder, F., Hoglund, P., Allison, J. P., Benoist, C. & Mathis, D. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulates the unfolding of autoimmune diabetes. J. Exp. Med. 187, 427–432 (1998).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  21. Yokochi, T., Holly, R. D. & Clark, E. A. B lymphoblast antigen (BB-1) expressed on Epstein Barr virus activated B cell blasts, b lymphoblastoid cell lines and Burkitts lymphomas. J. Immunol. 128, 823–827 (1982)

    CAS  PubMed  Google Scholar 

  22. Freedman, A. S., Freeman, G., Horowitz, J. C., Daley, J. & Nadler, L. B7, a B-cell-restricted antigen that identifies preactivated B cells. J. Immunol. 139, 3260–3267 (1987).

    CAS  PubMed  Google Scholar 

  23. Freeman, G. J. et al. Uncovering of functional alternative CTLA-4 counter-receptor in B7-deficient mice. Science 262, 907–909 (1993).

    Article  CAS  Google Scholar 

  24. Kozono, Y., Abe, R., Kozono, H., Kelly, R. G., Azuma, T. & Holers, V. M. Cross-linking CD21/CD35 or CD19 increases both B7-1 and B7-2 expression on murine splenic B cells. J. Immunol. 160, 1565–1572 (1998).

    CAS  PubMed  Google Scholar 

  25. Ikemizu S. et al. Structure and dimerization of a soluble form of B7-1. Immunity 12, 51–60 (2000).

    Article  CAS  Google Scholar 

  26. Sethna, M. P, van Parijs, L., Sharpe, A. H., Abbas, A. K. & Freeman, G. J. A negative regulatory function of B7 revealed in B7-1 transgenic mice. Immunity 1, 415–421 (1994).

    Article  CAS  Google Scholar 

  27. Khattri, R., Auger, J. A., Griffin, M. D., Sharpe, A. H. & Bluestone, J. A. Lymphoproliferative disorder in CTLA-4 knockout mice is characterized by CD28-regulated activation of Th2 responses. J. Immunol. 162, 5784–5791. (1999).

    CAS  PubMed  Google Scholar 

  28. Oosterwegel, M. A. et al. The role of CTLA-4 in regulating Th2 differentiation. J. Immunol. 163, 2634–2639 (1999).

    CAS  PubMed  Google Scholar 

  29. Corry, D. B., Reiner, S. L., Linsley, P. S. & Locksley, R. M. Differential effects of blockade of CD28-B7 on the development of Th1 or Th2 effector cells in experimental leishmaniasis. J. Immunol. 9, 4142–4148 (1994).

    Google Scholar 

  30. 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).

    Article  CAS  Google Scholar 

  31. Lenschow, D. J. et al. CD28/B7 regulation of Th1 and Th2 subsets in the development of autoimmune diabetes. Immunity 3, 285–293 (1996).

    Article  Google Scholar 

  32. Sayegh, M. H. et al. L.ACD28–B7 blockade after alloantigenic challenge in vivo inhibits Th1 cytokines but spares Th2. J. Exp. Med. 5, 1869–1874 (1995).

    Article  Google Scholar 

  33. Freeman, G. J. et al. B7-1 and B7-2 do not deliver identical costimulatory signals, because B7-2 but not B7-1 preferentially costimulates the initial production of IL-4. Immunity 5, 523–532 (1995).

    Article  Google Scholar 

  34. Kuchroo, V. K. et al. B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: application to autoimmune disease therapy. Cell 10, 707–718 (1995).

    Article  Google Scholar 

  35. Bird, J. J. et al. Helper T cell differentiation is controlled by the cell cycle. Immunity 9, 229–237 (1998).

    Article  CAS  Google Scholar 

  36. Randolph, D. A., Huang, G., Carruthers, C. J., Bromley, L. E. & Chaplin, D. D. The role of CCR7 in TH1 and TH2 cell localization and delivery of B cell help in vivo. Science 286, 2159–2162 (1999).

    Article  CAS  Google Scholar 

  37. D' Ambrosio, D. et al. Selective up-regulation of chemokine receptors CCR4 and CCR8 upon activation of polarized human type 2 Th cells. J. Immunol. 161, 5111–5115 (1998).

    CAS  Google Scholar 

  38. Salomon, B. et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 4, 431–440 (2000).

    Article  Google Scholar 

  39. 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. 6, 2762–2771 (1998).

    Google Scholar 

  40. Corry, D. B., Reiner, S. L., Linsley, P. S., Locksley, R. M. Differential effects of blockade of CD28-B7 on the development of Th1 or Th2 effector cells in experimental leishmaniasis. J. Immunol. 9, 4142–4148 (1994).

    Google Scholar 

  41. Tang, A., Judge, T. A., Nickoloff, B. J. & Turka, L. A. Suppression of murine allergic contact dermatitis by CTLA4Ig. Tolerance induction of Th2 responses requires additional blockade of CD40–ligand. J. Immunol. 1, 117–125 (1996).

    Google Scholar 

  42. Gause, W. C. et al. Polygyrus: B7-independence of the secondary type 2 response. Exp. Parasitol. 84, 264–273 (1996).

    Article  Google Scholar 

  43. London, C. A., Lodge, M. P. & Abbas, A. K. Functional responses and costimulator dependence of memory CD4+ T cells. J. Immunol. 164, 265–272 (2000).

    Article  CAS  Google Scholar 

  44. Henry, J., Miller, M. M. & Pontarotti, P. Structure and evolution of the extended B7 Family. Immunol. Today 6, 285–288 (1999).

    Article  Google Scholar 

  45. Swallow, M. M., Wallin, J. J. & Sha, W. C. B7h, a novel costimulatory homolog of B7.1 and B7.2, is induced by TNFα. Immunity 11, 423–432 (1999).

    Article  CAS  Google Scholar 

  46. Yoshinaga, S. K. et al. T-cell co-stimulation through B7RP-1 and ICOS. Nature 402, 827–832 (1999).

    Article  CAS  Google Scholar 

  47. Aicher, A. et al. Characterization of human inducible costimulator ligand expression and function. J. Immunol. 164, 4689–4696. (2000).

    Article  CAS  Google Scholar 

  48. Yoshinaga, S. K. et al. Characterization of a new human B7-related protein: B7RP-1 is the ligand to the co-stimulatory protein ICOS. Int. Immunol. 10, 1439–1447 (2000).

    Article  Google Scholar 

  49. Hutloff, A. et al. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 6716, 263–267 (1999).

    Article  Google Scholar 

  50. Coyle, A. J. et al. The CD28-related molecule ICOS is required for effective T cell-dependent immune responses. Immunity 1, 95–105 (2000).

    Article  Google Scholar 

  51. McAdam, A. J. et al. Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates differentiation of CD4(+) T cells. J. Immunol. 165, 5035–5040 (2000).

    Article  CAS  Google Scholar 

  52. Kopf, M. et al. Inducible costimulator protein (ICOS) controls T helper cell subset polarization after virus and parasite infection. J. Exp. Med. 192, 111–117 (2000)

    Article  Google Scholar 

  53. Dong, C. et al. ICOS costimulatory receptor is essential for T-cell activation and function Nature 409, 97–101 (2001).

    Article  CAS  Google Scholar 

  54. McAdam, A. J. et al. ICOS is critical for CD40 mediated antibody class Switching. Nature, 409, 102–105 (2001).

    Article  CAS  Google Scholar 

  55. Tafuri, A. et al. Essential role of ICOS in effective helper T cell responses. Nature 409, 105–109. (2001).

    Article  CAS  Google Scholar 

  56. Dong, H., Zhu, G., Tamada, K. & Chen, L. B7-H1 a third member of the B7 family, costimulates T cell proliferation and interleukin 10 secretion. Nature Med. 5, 1365–1369 (1999).

    Article  CAS  Google Scholar 

  57. Freeman, G. J. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192 1027–1034 (2000).

    Article  CAS  Google Scholar 

  58. Ishida, Y., Agata, Y., Shibahara, K. & Honjo, I. Induced expression of PD1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 11, 3887–3895 (1996).

    Article  Google Scholar 

  59. Latchman, Y. et al. PD-L2 is a second ligand for PD-1 and inhibits T cells activation. Nature Immunol. 2, 261–268 (2001).

    Article  CAS  Google Scholar 

  60. Kingsbury, G. et al. Identification and expression of the fifth member of the B7 family as a second ligand for programmed death –1 that inhibits cytokine production from T cells. J. Exp. Med. (in press the press, 2001).

  61. Nishimura, H., Minato, N., Nakano, T. & Honjo, T. Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses. Int. Immunol. 101563–10172 (1998).

  62. Nishimura, H., Nose, M., Hiai, H., Minato, N. & Honjo, T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11, 141–151 (1999).

    Article  CAS  Google Scholar 

  63. Agata, Y. et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int. Immunol. 8, 765–772 (1996)

  64. Chapoval, A. I. et al. B7-H3: A costimulatory molecule for T cell activation and IFN-γ production. Nature Immunol. 2, 269–274 (2001)

    Article  CAS  Google Scholar 

  65. Banchereau, J. & Steinman, R. M. Dendritic cells and the control of immunity. Nature 92, 245–249 (1998).

    Article  Google Scholar 

  66. Cella, M., Sallusto, F. & Lanzavecchia A. Origin, maturation and antigen presenting function of dendritic cells. Curr. Opin. Immunol. 9, 10–16 (1997).

    Article  CAS  Google Scholar 

  67. Gonzalo, J. A., Delaney, T., Corcoran, J., Gutierrez-Ramos, J. C. & Coyle, A. J. Complimentary and unique signals delivered by ICOS and CD28 regulate T cell effector function. J. Immunol. 166, 1–5 (2001).

    Article  CAS  Google Scholar 

  68. Hur, D. Y. et al. Role of follicular dendritic cells in the apoptosis of germinal center B cells. Immunol. Lett. 72, 107–111 (2000).

    Article  CAS  Google Scholar 

  69. Li, L. et al. Identification of a human follicular dendritic cell molecule that stimulates germinal center B cell growth. J. Exp. Med. 191, 1077–1084 (2000).

    Article  CAS  Google Scholar 

  70. Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).

    Article  CAS  Google Scholar 

  71. Schaerli, P. et al. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J. Exp. Med. 192, 1553–1562 (2000).

    Article  CAS  Google Scholar 

  72. Breitfeld D. et al. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J. Exp. Med. 192, 1545–1552 (2000).

    Article  CAS  Google Scholar 

  73. Mackay, C. R. Follicular homing T helper (Th) cells and the Th1/Th2 paradigm. J. Exp. Med. 192, 31–34 (2000).

    Article  Google Scholar 

Download references

Acknowledgements

We thank our colleagues and collaborators for their help and support in this work especially M. Kapsenburg, P. Limao Viera, G. Kingsbury, C. Fraser, J. Roftman, S. Manning, S. Tian and K. Kishimoto.

Author information

Authors and Affiliations

  1. Inflammation Division, Millennium Pharmaceuticals Inc., 45–75 Sidney St., Cambridge, 02139, MA, USA

    Anthony J. Coyle & Jose-Carlos Gutierrez-Ramos

Authors
  1. Anthony J. Coyle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jose-Carlos Gutierrez-Ramos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Anthony J. Coyle or Jose-Carlos Gutierrez-Ramos.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Coyle, A., Gutierrez-Ramos, JC. The expanding B7 superfamily: Increasing complexity in costimulatory signals regulating T cell function. Nat Immunol 2, 203–209 (2001). https://doi.org/10.1038/85251

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/85251

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing