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Immunologic Research

, Volume 15, Issue 1, pp 38–49 | Cite as

Immunosuppression through biockade of CD28:B7-mediated costimulatory signals

  • Thomas A. Judge
  • Aimin Tang
  • Laurence A. Turka
Article

Abstract

It is now well established that T cells require two signals for activation and effector function. The first signal is provided through the T cell receptor for antigen. The best-characterized pathway which provides the second, or costimulatory, signal is through the CD28 receptor on the surface of T cells. In vitro, ligation of the T cell receptor without a second signal induces a long-lived state of anergy in T cells. CD28 has two known ligands, B7-1 and B7-2, expressed on activated antigen-presenting cells. A soluble fusion protein called CTLA4Ig has been produced which binds B7-1 and B7-2 and acts as a competitive inhibitor of CD28. In vitro and in vivo studies with CTLA4Ig demonstrate that it is an extremely effective immunosuppressive agent in models of transplantation and autoimmunity. Mechanistic studies indicate that CTLA4Ig may work by partially inhibiting the expansion of antigen-reactive cells and inducing anergy in the residual population.

Key Words

T cells CTLA4Ig Tolerance, transplantation Anergy 

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References

  1. 1.
    Davis MM, Bjorkman PJ: T-cell antigen receptor genes and T-cell recognition. Nature 1988;334:395–402.PubMedCrossRefGoogle Scholar
  2. 2.
    Falk K, Rotzsche O, Stevanovic S, Jung G, Rammensee HG: Allele-specific motifs revealed by sequencing of self peptides eluted from MHC molecules. Nature 1991;351: 290–296.PubMedCrossRefGoogle Scholar
  3. 3.
    Matis LA: The molecular basis of T-cell specificity. Annu Rev Immunol 1990;8:65.PubMedCrossRefGoogle Scholar
  4. 4.
    Janeway CH, Bottomly K: Signals and signs for lymphocyte responses. Cell 1994;76:275–285.PubMedCrossRefGoogle Scholar
  5. 5.
    Scwartz RH: A cell culture model for T lymphocyte clonal anergy. Science 1990;248:1349–1356.CrossRefGoogle Scholar
  6. 6.
    June CH, Bluestone JA, Nadler LM, Thompson CB: The B7 and CD28 receptor families. Immunol Today 1994;15:321–331.PubMedCrossRefGoogle Scholar
  7. 7.
    Linsley P, Clark E, Ledbetter J: T cell antigen CD28 mediates adhesion with B cells by interacting with activation antigen B7/BB-1. Proc Natl Acad Sci USA 1990;87:5031–5035.PubMedCrossRefGoogle Scholar
  8. 8.
    Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA: CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 1991;174:561–569.PubMedCrossRefGoogle Scholar
  9. 9.
    Harper K, Balzano C, Rouvier E, Mattei M, Luciani M, Golstein P: cTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location. J Immunol 1991;147:1037–1044.PubMedGoogle Scholar
  10. 10.
    Howard T, Rochelle J, Seldin M: CD28 and CTLA-4, two related members of the Ig supergene family, are tightly linked on proximai mouse chromosome 1. Immunogenetics 1991;33:74–76.PubMedCrossRefGoogle Scholar
  11. 11.
    Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, Thompson CB, Bluestone JA: CTLA-4 can function as a negative regulator of T cell activation. Immunity 1994;1:405–413.PubMedCrossRefGoogle Scholar
  12. 12.
    Azuma M, Ito D, Yagita H, Okumura K, Phillips JH, Lanier LL, Somoza C: B70 antigens is a second ligand for CTLA-4 and CD28. Nature 1993;366:76–79.PubMedCrossRefGoogle Scholar
  13. 13.
    Freeman G, Gribben J, Boussiotis V, et al: Cloning of B7-2: ACTLA-4 counter receptor that costimulates human T cell preliferation. Science 1993;262:909–911.PubMedCrossRefGoogle Scholar
  14. 14.
    Hathcock K, Laszio G, Pucillo C, Linsley P, Hodes R: Comparative analysis of B7-1 and B7-2 costimulatory ligands: Expression and function. J Exp Med 1994;180:631–640.PubMedCrossRefGoogle Scholar
  15. 15.
    Guihan EC, Gribben JG, Boussiotis VA, Freeman GJ, Nadler LM: Pivotal role of the B7:CD28 pathway in transplantation tolerance and tumor immunity. Blood 1994;84:3261–3282.Google Scholar
  16. 16.
    Kuchroo VK, Das DP, Brown JA, Ranger AM, Zamvil SS, Sobel RA, Weiner HL, Nabavi N, Glimeber LH: B7-1 and B7-2 costimulatory molecules activated differentially the Th1/Th2 development pathways: Application to autoimmune disease therapy. Cell 1995;80:707–718.PubMedCrossRefGoogle Scholar
  17. 17.
    Turka LA, Linsley PS, Lin H, Brady W, Leiden JM, Wei R-Q, Gibson ML, Zheng X-G, Myrdal S, Gordon D, Bailey T, Bolling SF, Thompson CB: T cell activation by the CD28-ligand B7 is required for cardiac allograft rejection in vivo. Proc Nat Acad Sci USA 1992;89:11102–11105.PubMedCrossRefGoogle Scholar
  18. 18.
    Lenschow D, Zeng Y, Thistlethwaite R, Montag A, Brady W, Gibson MG, Linsley PS, Bluestone JA: Long-term survival of xenogenic pancreatic islet grafts induced by CTLA4Ig. Science 1992;257:789–792.PubMedCrossRefGoogle Scholar
  19. 19.
    Lin H, Bolling SF, Linsley PS, Wei R, Gordon D, Thompson CB, Turka LA: Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus doncr-specific transfusion. J Exp Med 1993;178: 1801–1806PubMedCrossRefGoogle Scholar
  20. 20.
    Sayegh MH, Akalin E, Hancock WW, Russell ME, Carpenter CB, Linsley PS, Turka LA: CD28-B7 blockade after alloantigenic chailenge in vivo inhibits Th1 cytokines but spaces Th2. J Exp Med 1995; 181:1869–1874.PubMedCrossRefGoogle Scholar
  21. 21.
    Finck BK, Linsley PS, Wolsy D: Treatment of murine lupus with CTLA4Ig. Science 1994;265:1225–1227.PubMedCrossRefGoogle Scholar
  22. 22.
    Perrin P, Scott D, Quigley L, et al. Role of B7:CD28/CTLA-4 in the induction of chronic relapsing experimental allergic encephalomyelitis. J Immunol 1995;154:1481–1490.PubMedGoogle Scholar
  23. 23.
    Lenschow D, Ho S, Satter H, et al.: Differential effects of anti-B7-1 and anti-B7-2 monoclonal antibody treatment on the development of diabetes in the nonbese diabetic mouse. J Exp Med 1995;181:1145–1155.PubMedCrossRefGoogle Scholar
  24. 24.
    Wallace P, Johnson J, MacMaster J, Konnedy K, Gladstone P, Linsley P: CTLA4Ig treatment ameliorates the lethality of murine graft-versus-host. disease across major histocompatibility complex barriers. Transplantation 1994;58:602–610.PubMedCrossRefGoogle Scholar
  25. 25.
    Miller RG: An immunological suppressor cell inactivating cytotoxic T-lymphocyte precursor cells recogrizing it. Nature 1980;287:544–546.PubMedCrossRefGoogle Scholar
  26. 26.
    Boise LH, Minn AJ, Noel PJ, June, CH, Accavitti MA, Lindsten T, Thompson CB: CD28 costimulation can promote T cell survival by enhancing the expression of bcl-xL. Immunity 1995;3:87–98.PubMedCrossRefGoogle Scholar
  27. 27.
    Browning MJ, Huang AS, et al.: Cytolytic T lymphocytes from the BALB/c-H-2dm2 mouse recognize the vesicular stomatitis virus glycoprotein and are restricted by class II MHC antigens. J Immunol 1990; 145:985–994.PubMedGoogle Scholar
  28. 28.
    McCormack JE, Kappier J, Marrack P: Stimulation with specific antigen can block superantigen-mediated deletion of T cells in vivo. Proc Nat Acad Sci USA 1994;91:2986–2090.CrossRefGoogle Scholar
  29. 29.
    Kumar V, Sercarz EE: The involvement of T cell receptor peptide-specific regulatory CD4+ T cells in recovery from antigen-induced autoimmune disease. J Exp Med 1993; 178:909–916.PubMedCrossRefGoogle Scholar
  30. 30.
    Murphy KM, Heimberger AB, Loh DY: Induction by antigen of intrathymic apoptosis of CD4+CD8+ TCRlo thymocytes in vivo. Science 1990;1990:1720–1723.CrossRefGoogle Scholar
  31. 31.
    Kearney ER, Paper KA, Loh DY, Jenkins MK: Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo. Immunity 1994;1:327–339.PubMedCrossRefGoogle Scholar
  32. 32.
    Kearney ER, Walunas TL, Karr RW, Morton PA, Loh DY, Bluestone JA, Jenkins MK: 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 1995; 155:1032–1036.PubMedGoogle Scholar
  33. 33.
    Yang X, Hayglass K: A simple, sensitive, dual mAb based ELISA for murine gamma interferon determination: Comparison with two common bioassays. J Immunol 1993;14: 129–148.Google Scholar
  34. 34.
    Morris SC, Madden KB, Adamoviez JJ, Gause WC, Hubbard BR, Gately MK, Finkelman FD: Effects of IL-2 on in vivo cytokine gene expression and Ig isotype selection. J Immunol 1994;152:1047–1056.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 1996

Authors and Affiliations

  • Thomas A. Judge
    • 1
  • Aimin Tang
    • 1
  • Laurence A. Turka
    • 1
    • 2
  1. 1.Department of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Institute for Human Gene TherapyUniversity of PennsylvaniaPhiladelphiaUSA

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