Immunosuppression and the CD28 receptor


The CD28 and CTLA-4 molecules on T cells and their counterreceptors, B7-1 and B7-2, on antigen-presenting cells constitute an important costimulatory pathway for immune responses to antigen in vitro and in vivo. A primary function of these interactions is to regulate production of T-cell-derived cytokines, including interleukin 2. A soluble form of the CTLA-4 receptor, CTLA4Ig, has been produced which binds B7 with high avidity and functions as a competitive inhibitor of CD28/CTLA-4 interactions. In rodent models, CTLA4Ig inhibits T-dependent antibody responses, blocks organ graft rejection, prevents death from acute graft-versus-host disease, and prevents autoimmune disease. CTLA4Ig has a novel mechanism of action, and also has several attractive features for an immunosuppressive drug, including low toxicity, long serum half-life, and the ability to induce long-lasting antigen-specific immune suppression (tolerance) after therapy. CTLA4Ig thus represents a prototype of a new class of immunosuppressive drugs which function by blocking T-cell costimulation through the CD28 receptor.

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


  1. 1

    Liu, Y. and Linsley, P.S., Curr. Opin. Immunol., 4 (1992) 265.

    Google Scholar 

  2. 2

    Bretscher, P. and Cohn, M., Science, 169 (1970) 1042.

    Google Scholar 

  3. 3

    Lafferty, K.J., Prowse, S.J. and Simeonovic, C.J., Annu. Rev. Immunol., 1 (1983) 143.

    Google Scholar 

  4. 4

    Schwartz, R.H., Science, 248 (1990) 1349.

    Google Scholar 

  5. 5

    Liu, Y. and Janeway Jr., C.A., J. Exp. Med., 172 (1990) 1735.

    Google Scholar 

  6. 6

    Van Seventer, G.A., Shimizu, Y. and Shaw, S., Curr. Opin. Immunol., 3 (1991) 294.

    Google Scholar 

  7. 7

    Linsley, P.S. and Ledbetter, J.A., Annu. Rev. Immunol., 11 (1993) 191.

    Google Scholar 

  8. 8

    June, C.H., Ledbetter, J.A., Linsley, P.S. and Thompson, C.B., Immunol. Today, 11 (1990) 211.

    Google Scholar 

  9. 9

    Linsley, P.S., Clark, E.A. and Ledbetter, J.A., Proc. Natl. Acad. Sci. USA, 87 (1990) 5031.

    Google Scholar 

  10. 10

    Freeman, G.J., Freedman, A.S., Segil, J.M., Lee, G., Whitman, J.F. and Nadler, L.M., J. Immunol., 143 (1989) 2714.

    Google Scholar 

  11. 11

    Linsley, P.S., Brady, W., Grosmaire, L.A., Aruffo, A., Damle, N.K. and Ledbetter, J.A., J. Exp. Med., 173 (1991) 721.

    Google Scholar 

  12. 12

    Brunet, J.-F., Denizot, F., Luciani, M.-F., Roux-Dosseto, M., Suzan, M., Mattei, M.-G. and Golstein, P., Nature, 328 (1987) 267.

    Google Scholar 

  13. 13

    Linsley, P.S., Brady, W., Urnes, M., Grosmaire, L.S., Damle, N.K. and Ledbetter, J.A., J. Exp. Med., 174 (1991) 561.

    Google Scholar 

  14. 14

    Shahinian, A., Pfeffer, K., Lee, K.P., Kundig, T.M., Kishihara, K., Wakeham, A., Kawai, K., Ohashi, P.S., Thompson, C.B. and Mak, T.W., Science, 261 (1993) 609.

    Google Scholar 

  15. 15

    Harding, F.A., McArthur, J.G., Gross, J.A., Raulet, D.H. and Allison, J.P., Nature, 356 (1992) 607.

    Google Scholar 

  16. 16

    Tan, P., Anasetti, C., Hansen, J.A., Melrose, J., Brunvand, M., Bradshaw, J., Ledbetter, J.A. and Linsley, P.S., J. Exp. Med., 177 (1993) 165.

    Google Scholar 

  17. 17

    Gimmi, C.D., Freeman, G.J., Gribben, J.G., Gray, G. and Nadler, L.M., Proc. Natl. Acad. Sci. USA, 90 (1993) 6586.

    Google Scholar 

  18. 18

    Linsley, P.S., Greene, J.L., Tan, P., Bradshaw, J., Ledbetter, J.A., Anasetti, C. and Damle, N.K., J. Exp. Med., 176 (1992) 1595.

    Google Scholar 

  19. 19

    Balzano, C., Buonavista, N., Rouvier, E. and Golstein, P., Int. J. Cancer, S7 (1992) 1.

    Google Scholar 

  20. 20

    Freeman, G.J., Lombard, D.B., Gimmi, C.D., Brod, S.A., Lee, K., Laning, J.C., Hafler, D.A., Dorf, M.E., Gray, G.S., Reiser, H., June, C.H., Thompson, C.B. and Nadler, L.M., J. Immunol., 149 (1992) 3795.

    Google Scholar 

  21. 21

    Inobe, M., Linsley, P.S., Ledbetter, J.A., Nagai, Y., Tamakoshi, M. and Uede, T., Biochem. Biophys. Res. Commun., 200 (1994) 243.

    Google Scholar 

  22. 22

    Wu, Y., Guo, Y. and Liu, Y., J. Exp. Med., 178 (1993) 1789.

    Google Scholar 

  23. 23

    Hathcock, K.S., Laszlo, G., Bradshaw, J., Linsley, P.S. and Hodes, R., Science, 262 (1993) 905.

    Google Scholar 

  24. 24

    Freeman, G.J., Boriello, F., Reiser, H., Kim, J., Du, L., McKnight, A., Lombard, D., Gray, G., Nadler, L.M. and Sharpe, A., Science, (1994) in press.

  25. 25

    Valle, A.P., Garrone, H.Y., Bonnefoy, J.-Y., Freedman, A.S., Freeman, G., Nadler, L.M. and Banchereau, J., Immunology, 69 (1990) 531.

    Google Scholar 

  26. 26

    Sansom, D.M. and Hall, N.D., Eur. J. Immunol., 23 (1993) 295.

    Google Scholar 

  27. 27

    Azuma, M., Cayabyab, M., Buck, D., Phillips, J.H. and Lanier, L., J. Exp. Med., 177 (1993) 845.

    Google Scholar 

  28. 28

    Haffar, O.K., Smithgall, M.D., Bradshaw, J., Brady, B., Damle, N.K. and Linsley, P.S., Proc. Natl. Acad. Sci. USA, 90 (1993) 11094.

    Google Scholar 

  29. 29

    Linsley, P.S., Wallace, P.M., Johnson, J., Gibson, M.G., Greene, J.L., Ledbetter, J.A., Singh, C. and Tepper, M.A., Science, 257 (1992) 792.

    Google Scholar 

  30. 30

    Turka, L.A., Linsley, P.S., Lin, H., Brady, W., Leiden, J.M., Wei, R.-Q., Gibson, M.L., Zheng, X.-G., Myrdal, S., Gordon, D., Bailey, T., Bolling, S. and Thompson, C.B., Proc. Natl. Acad. Sci. USA, 89 (1992) 11102.

    Google Scholar 

  31. 31

    Lin, H., Bolling, S.F., Linsley, P.S., Wei, R.-Q., Gordon, D., Thompson, C.B. and Turka, L.A., J. Exp. Med., 178 (1993) 1801.

    Google Scholar 

  32. 32

    Lenschow, D.J., Zeng, Y., Thistlewaite, J.R., Montag, A., Brady, W., Gibson, M.G., Linsley, P.S. and Bluestone, J.A., Science, 257 (1992) 789.

    Google Scholar 

  33. 33

    Wallace, P.M., Johnson, J., MacMaster, J., Kennedy, K., Gladstone, P. and Linsley, P.S., Transplantation, (1994) in press.

  34. 34

    Nishakawa, K., Linsley, P.S., Clooins, A.B., Stamenkovic, I., McCluskey, R.T. and Andres, G., Eur. J. Immunol., (1994) in press.

  35. 35

    Freeman, G.J., Gray, G.S., Gimmi, C.D., Lombard, D.B., Zhou, L.-J., White, M., Fingeroth, J.D., Gribben, J.G. and Nadler, L.M., J. Exp. Med., 174 (1991) 625.

    Google Scholar 

Download references

Author information



Rights and permissions

Reprints and Permissions

About this article

Cite this article

Linsley, P.S. Immunosuppression and the CD28 receptor. Perspectives in Drug Discovery and Design 2, 221–231 (1994).

Download citation

Key words

  • CTLA-4
  • B7
  • T-cell costimulation