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A structure-based approach to designing synthetic CD8α peptides that can inhibit cytotoxic T-lymphocyte responses

Nature Medicine volume 4, pages 309–314 (1998)Cite this article

Abstract

CD8 molecules function as co-receptors on cytotoxic T lymphocytes (CTLs), interacting with a nonpolymorphic region of the major histocompatibility complex (MHC) class I a3 domain on antigen-presenting cells. Analogues were designed from a structural model of the mouse CD8α molecule to identify surfaces involved in CD8 function. Peptides were screened for in vitro biological activity on alloreactive CTLs, and analogue SC4 (p54–59) was found to be inhibitory during both the generation and effector stages. SC4 was also able to significantly prolong skin al log raft survival across a MHC class I barrier. Thus, such CD8αnalogues may have therapeutic potential as immunoregulators of CTL immune responses.

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References

  1. Doherty, P.C. T cells and viral infections. Br. Med. Bull. 41, 7–14 (1985).

    Article  CAS  Google Scholar 

  2. Tanaka, K., Yoshioka, T., Bieberich, C. & Jay, C. Role of the major histocompatibility complex class I antigens in tumor growth and metastasis. Annu. Rev. Immunol. 6, 359–380 (1988).

    Article  CAS  Google Scholar 

  3. Mason, D.W. & Morris, P.J. Effector mechanisms in allograft rejection. Annu. Rev. Immunol. 4, 119–145 (1986).

    Article  CAS  Google Scholar 

  4. Zinkernagel, R.M. & Doherty, P.C. H-2 compatibility requirement for T-cell-medi-ated lysis of target cells infected with lymphocytic choriomeningitis virus: Different cytotoxic T-cell specificities are associated with structures coded for in H-2K or H-2D. J. Exp. Med. 141, 1427–1436 (1975).

    Article  CAS  Google Scholar 

  5. Miceli, M.C. & Parnes, J.R. Role of CD4 and CD8 in T cell activation and differentiation. Adv. Immunol. 53, 59–122 (1993).

    Article  CAS  Google Scholar 

  6. Norment, A.M., Salter, R.D., Parham, P., Engelhard, V.H. & Littman, D.R. Cell-cell adhesion mediated by CD8αnd MHC class I molecules. Nature 336, 79–81 (1988).

    Article  CAS  Google Scholar 

  7. Salter, R.D. et al. A binding site for the T-celi co-receptor CD8 on the alpha 3 domain of HLA-A2. Nature 345, 41–46 (1990).

    Article  CAS  Google Scholar 

  8. Veillette, A., Bookman, M.A., Horak, E.M. & Bolen, J.B. The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56lck . Cell 55, 301–308 (1988).

    Article  CAS  Google Scholar 

  9. Zamoyska, R. et al. Inability of CD8αlpha polypeptides to associate with p56lck correlates with impaired function in vitro and lack of expression in vivo . Nature 342, 278–281 (1989).

    Article  CAS  Google Scholar 

  10. Parnes, J.R. Molecular biology and function of CD4 and CD8. Immunol. 44, 265–305 (1989).

    CAS  Google Scholar 

  11. Hunkapiller, T. & Hood, L. Diversity of the immunoglobulin gene superfamily. Adv. Immunol. 44, 1–63(1989).

    Article  CAS  Google Scholar 

  12. Williams, A.F. & Barclay, A.N. The immunoglobulin superfamily—domains for cell surface recognition. Ann. Rev. Immunol. 6, 381–405 (1988).

    Article  CAS  Google Scholar 

  13. Sukhatme, V.P., Sizer, K.C., Vollmer, A.C., Hunkapiller, T. & Parnes, J.R. The T cell differentiation antigen Leu-2/T8 is homologous to immunoglobulin and T cell receptor variable regions. Cell 40, 591–597 (1985).

    Article  CAS  Google Scholar 

  14. Nakauchi, H. et al. Molecular cloning of Lyt-2, a membrane glycoprotein marking a subset of mouse T lymphocytes: molecular homology to its human counterpart, Leu-2/T8, and to immunoglobulin variable regions. Proc. Natl. Acad. Sci. USA 82, 5126–5130(1985).

    Article  CAS  Google Scholar 

  15. Leahy, D.J., Axel, R. & Hendrickson, W.A. Crystal structure of a soluble form of the human T cell co-receptor CD8αt 2. 6 Å resolution. Cell 68, 1145–1162 (1992).

    Article  CAS  Google Scholar 

  16. Jameson, B.A., McDonnell, J.M., Marini, J.C. & Korngold, R. A rationally designed CD4 analogue inhibits experimental allergic encephalomyelitis. Nature 368, 744–746 (1994).

    Article  CAS  Google Scholar 

  17. Jameson, B.A. Modelling in peptide design. Nature 341, 465–466 (1989).

    Article  CAS  Google Scholar 

  18. Sanders, S.K., Fox, R.O. & Kavathas, P. Mutations in CD8 that affect interactions with HLA class I and monoclonal anti-CD8αntibodies. J. Exp. Med. 174, 371–379 (1991).

    Article  CAS  Google Scholar 

  19. Franco, M.D. et al. Regions of the CD8 molecule involved in the regulation of CD2-mediated activation. Cell. Immunol. 157, 341–352 (1994).

    Article  CAS  Google Scholar 

  20. Giblin, P.A., Leahy D.J., Mennone, J. & Kavathas, P.B. The role of charge and multiple faces of the CD8 alpha/alpha homodimer in binding to major histocompati-bility complex class I molecules: Support for a bivalent model. Proc. Natl. Acad. Sci. USA 91, 1716–1720 (1994).

    Article  CAS  Google Scholar 

  21. Clayberger, C., Lyu, S.C., DeKruyff, R., Parham, P. & Krensky,, A.M. Peptides corresponding to the CD8αnd CD4 binding domains of HLA molecules block T lymphocyte immune responses in vitro. Immunol. 153, 946–951 (1994).

    CAS  Google Scholar 

  22. Emmrich, F., Strittmatter, U. & Eichmann, K. Synergism in the activation of human CD8 T cells by cross-linking the T-cell receptor complex with the CDS differentiation antigen. Proc. Natl. Acad. Sci. USA 83, 8298–8302 (1986).

    Article  CAS  Google Scholar 

  23. Gao, G.F., et al. Crystal structure of the complex between human CD8αoc and HLA-A2. Nature 387, 630–634 (1997).

    Article  CAS  Google Scholar 

  24. Fung-Leung, W.P., et al. The lack of CD8αlpha cytoplasmic domain resulted in a dramatic decrease in efficiency in thymic maturation but only a moderate reduction in cytotoxic function of CD8+ T lymphocytes. Eur J. Immunol. 23, 2834–2840 (1994).

    Article  Google Scholar 

  25. Eichmann, K. et al. Affinity enhancement and transmembrane signaling are associated with distinct epitopes on the CD8αlpha beta heterodimer. J. Immunol. 147, 2075–2081 (1991).

    CAS  PubMed  Google Scholar 

  26. Connolly, J.M., Hansen, T.H., Ingold, A.L. & Potter, T.A. Recognition by CD8 on cy-totoxic T lymphocytes is ablated by several substitutions in the class I alpha 3 domain: CD8αnd the T-cell receptor recognize the same class I molecule. Proc. Natl. Acad. Sci. USA 87, 2137–2141 (1990).

    Article  CAS  Google Scholar 

  27. Mescher, M.F. Molecular interactions in the activation of effector and precursor cytotoxic T lymphocytes. Immunol. Rev. 146, 177–210 (1995).

    Article  CAS  Google Scholar 

  28. Cai, Z. & Sprent, J. Resting and activated T cells display different requirements for CD8 molecules. J. Exp. Med. 179, 2005–2015 (1994).

    Article  CAS  Google Scholar 

  29. O'Rourke, A.M. & Mescher, M.F. Signals for activation of CD8-dependent adhesion and costimulation in CTLs. J. Immunol. 152, 4358–4367 (1994).

    CAS  PubMed  Google Scholar 

  30. Zamoyska, R., Vollmer, A.C., Sizer, K.C., Liaw, C.W. & Parnes, J.R., Lyt-2 polypeptides arise from a single gene by alternative splicing patterns of mRNA. Cell 43, 153–163 (1985).

    Article  CAS  Google Scholar 

  31. Karplus, M. & Petsko, G.A. Molecular dynamics simulations in biology. Nature 347, 631–639 (1989).

    Article  Google Scholar 

  32. McDonnell, J.M., Blank,, K.J., Rao,, P.E. & Jameson,, B.A. Direct involvement of the CDR3-like domain of CD4 in T helper cell activation. J. Immunol. 149, 1626–1630 (1992).

    CAS  Google Scholar 

  33. Bailey, D.W. & Usama,, B. A. rapid method of grafting skin on tails of mice. Transplant. Bull. 7, 424–425 (1960).

    Article  CAS  Google Scholar 

  34. Sprent, J., Schaefer, M., Lo, D. & Korngold, R. Properties of purified T cell subsets In vivo responses to class I vs. class II H-2 differences. J. Exp. Med. 163, 998–1011 (1986).

    Article  Google Scholar 

  35. Kraulis, P.J. MOLSCRIPT: A program to produce both detailed and schematic plots of protein structures. J. Appl. Crystallogr. 24, 946–950 (1991).

    Article  Google Scholar 

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Authors and Affiliations

  1. Kimmel Cancer Institute, Jefferson Medical College, 233 S. 10th Street, Philadelphia, Pennsylvania, 19107, USA

    Swati Choksi, Bradford A. Jameson & Robert Korngold

  2. Allegheny University, 245 N. 15th Street, College Building, Philadelphia, Pennsylvania, 19102, USA

    Bradford A. Jameson

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  1. Swati Choksi
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  2. Bradford A. Jameson
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  3. Robert Korngold
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Choksi, S., Jameson, B. & Korngold, R. A structure-based approach to designing synthetic CD8α peptides that can inhibit cytotoxic T-lymphocyte responses. Nat Med 4, 309–314 (1998). https://doi.org/10.1038/nm0398-309

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