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Rational design of cytotoxic T-cell inhibitors

Nature Biotechnology volume 18, pages 984–988 (2000)Cite this article

Abstract

This study describes the use of the CD8/major histocompatibility complex (MHC) class I crystal structure as a template for the de novo design of low-molecular-weight surface mimetics. The analogs were designed from a local surface region on the CD8 α-chain directly adjacent to the bound MHC class I, to block the protein associations in the T-cell activation cluster that occur upon stimulation of the cytotoxic T lymphocytes (CTLs). One small conformationally restrained peptide showed dose-dependent inhibition of a primary allogeneic CTL assay while having no effect on the CD4-dependent mixed lymphocyte reaction (MLR). The analog's activity could be modulated through subtle changes in its side chain composition. Administration of the analog prevented CD8-dependent clearance of a murine retrovirus in BALB/c mice. In C57BL/6 mice challenged with the same retrovirus, the analog selectively inhibited the antiviral CTL responses without affecting the ability of the CTLs to generate robust allogeneic responses.

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Figure 1: Surface structure of the human and murine CD8 α-chains.
Figure 2: Titration of the RDT-derived analogs in a CD8-dependent CTL assay.
Figure 3: Structure–activity relationship (SAR) study of the cRDTc analog.
Figure 4: E-55+ MuLV viral clearance assay in BALB/c mice.
Figure 5: E-55+ MuLV target response assay in C57BL/6 mice.

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References

  1. Hehmke, B., Michaelis, D., Gens, E., Laube, F. & Kohnert, K.D. Aberrant activation of CD8+ T-cell and CD8+ T-cell subsets in patients with newly diagnosed IDDM. Diabetes 44, 1414–1419 (1995).

    Article  CAS  Google Scholar 

  2. Peakman, M., Leslie, R.D., Alviggi, L., Hawa, M. & Vergani, D. Persistent activation of CD8+ T cells characterizes prediabetic twins. Diabetes Care 19, 1177–1184 (1996).

    Article  CAS  Google Scholar 

  3. Yoneda, R. et al. CD8 cytotoxic T-cell clone rapidly transfers autoimmune diabetes in very young NOD and MHC class I-compatible scid mice. Diabetologia 40, 1044–1052 (1997).

    Article  CAS  Google Scholar 

  4. DiLorenzo, T.P. et al. Major histocompatibility complex class I-restricted T cells are required for all but the end stages of diabetes development in nonobese diabetic mice and use a prevalent T-cell receptor alpha chain gene rearrangement. Proc. Natl. Acad. Sci. USA 95, 12538–12543 (1998).

    Article  CAS  Google Scholar 

  5. Rabinovitch, A. & Suarez-Pinzon, W.L. Cytokines and their roles in pancreatic islet beta-cell destruction and insulin-dependent diabetes mellitus. Biochem. Pharmacol. 55, 1139–1149 (1998).

    Article  CAS  Google Scholar 

  6. Wong, F.S. & Janeway, C.A. Jr., The role of CD4 vs. CD8 T cells in IDDM. J. Autoimmun. 13, 290–295 (1999).

    Article  CAS  Google Scholar 

  7. He, G. et al. Differential effect of an anti-CD8 monoclonal antibody on rejection of murine intestine and cardiac allografts. Transplant. Proc. 31, 1239–1241 (1999).

    Article  CAS  Google Scholar 

  8. Fowler, D.H. & Gress, R.E. CD8+ T cells of Tc2 phenotype mediate a GVL effect and prevent marrow rejection. Vox Sang 74 Suppl. 2, 331–340 (1998).

    Article  CAS  Google Scholar 

  9. Beyers, A.D., Spruyt, L.L. & Williams, A.F. Molecular associations between the T-lymphocyte antigen receptor complex and the surface antigens CD2, CD4, or CD8 and CD5. Proc. Natl. Acad. Sci. USA 89, 2945–2949 (1992).

    Article  CAS  Google Scholar 

  10. Wheeler, C.J., Chen, J.Y., Potter, T.A. & Parnes, J.R. Mechanisms of CD8 beta-mediated T cell response enhancement: interaction with MHC class I/beta2-microglobulin and functional coupling to TCR/CD3. J. Immunol. 160, 4199–4207 (1998).

    CAS  PubMed  Google Scholar 

  11. Kwan Lim, G.E., McNeill, L., Whitley, K., Becker, D.L. & Zamoyska, R. Co-capping studies reveal CD8/TCR interactions after capping CD8 beta polypeptides and intracellular associations of CD8 with p56(lck). Eur. J. Immunol. 28, 745–754 (1998).

    Article  CAS  Google Scholar 

  12. Janeway, C.A. Jr., The T cell receptor as a multicomponent signalling machine: CD4/CD8 coreceptors and CD45 in T cell activation. Annu. Rev. Immunol. 10, 645–674 (1992).

    Article  CAS  Google Scholar 

  13. Parnes, J.R. Molecular biology and function of CD4 and CD8. Adv. Immunol. 44, 265–311 (1989).

    Article  CAS  Google Scholar 

  14. Gao, G.F. et al. Crystal structure of the complex between human CD8 alpha(alpha) and HLA-A2. Nature 387, 630–634 (1997).

    Article  CAS  Google Scholar 

  15. Kern, P.S. et al. Structural basis of CD8 coreceptor function revealed by crystallographic analysis of a murine CD8 alphaalpha ectodomain fragment in complex with H-2Kb. Immunity 9, 519–530 (1998).

    Article  CAS  Google Scholar 

  16. Boriack-Sjodin, P.A., Margarit, S.M., Bar-Sagi, D. & Kuriyan, J. The structural basis of the activation of Ras by Sos (see comments). Nature 394, 337–343 (1998).

    Article  CAS  Google Scholar 

  17. de Vos, A.M., Ultsch M. & Kossiakoff A.A. Human growth hormone and extracellular domain of its receptor: crystal structure of the complex. Science 255(5042), 306–312 (1992).

    Article  CAS  Google Scholar 

  18. Banner, D.W. et al. Crystal structure of the soluble human 55 kd TNF receptor–human TNF beta complex: implications for TNF receptor activation. Cell 73, 431–445 (1993).

    Article  CAS  Google Scholar 

  19. Kwong, P.D. et al. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody (see comments). Nature 393, 648–659 (1998).

    Article  CAS  Google Scholar 

  20. Rittinger, K., Walker, P.A., Eccleston, J.F., Smerdon, S.J. & Gamblin, S.J. Structure at 1.65 Å of RhoA and its GTPase-activating protein in complex with a transition-state analogue (see comments). Nature 389, 758–762 (1997).

    Article  CAS  Google Scholar 

  21. Cheng, Y.K. & Rossky, P.J. Surface topography dependence of biomolecular hydrophobic hydration. Nature 392, 696–699 (1998).

    Article  CAS  Google Scholar 

  22. Pardanani, A., Gambacurta, A., Ascoli, F. & Royer, W.E. Jr., Mutational destabilization of the critical interface water cluster in Scapharca dimeric hemoglobin: structural basis for altered allosteric activity. J. Mol. Biol. 284, 729–739 (1998).

    Article  CAS  Google Scholar 

  23. Leahy, D.J., Axel, R. & Hendrickson, W.A. Crystal structure of a soluble form of the human T cell coreceptor CD8 at 2.6 A resolution. Cell 68, 1145–1162 (1992).

    Article  CAS  Google Scholar 

  24. Avidan, N., Sieck, T.G. & Blank, K.J. Role of T-cell subsets in acute and persistent E-55+ murine leukemia virus infection in susceptible progressor and resistant long-term nonprogressor mouse strains. Women and Infants Transmission Study. Clin. Immunol. Immunopathol. 85, 282–288 (1997).

    Article  CAS  Google Scholar 

  25. Panoutsakopoulou, V., Little, C.S., Sieck, T.G., Blankenhorn, E.P. & Blank, K.J. Differences in the immune response during the acute phase of E-55+ murine leukemia virus infection in progressor BALB and long-term nonprogressor C57BL mice. J. Immunol. 161, 17–26 (1998).

    CAS  PubMed  Google Scholar 

  26. Rockwell, A.L. et al. Rapid synthesis of RGD mimetics with isoxazoline scaffolds on solid phase: identification of alphavbeta3 antagonists lead compounds. Bioorg. Med. Chem. Lett. 9, 937–942 (1999).

    Article  CAS  Google Scholar 

  27. Xue, C.B. et al. Design, synthesis, and in vitro activities of benzamide-core glycoprotein IIb/IIIa antagonists: 2,3-diaminopropionic acid derivatives as surrogates of aspartic acid. Bioorg. Med. Chem. 5, 693–705 (1997).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  30. Matzinger, P. The JAM test. A simple assay for DNA fragmentation and cell death. J. Immunol. Methods 145, 185–192 (1991)

    Article  CAS  Google Scholar 

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Author notes

  1. C. Scott Little

    Present address: Philadelphia College of Osteopathic Medicine, Philadelphia, PA

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Cancer Center, School of Medicine, MCP Hahnemann University, Philadelphia, 19102, PA

    Anna P. Tretiakova, C. Scott Little, Kenneth J. Blank & Bradford A. Jameson

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  1. Anna P. Tretiakova
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  2. C. Scott Little
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  3. Kenneth J. Blank
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Correspondence to Bradford A. Jameson.

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Tretiakova, A., Little, C., Blank, K. et al. Rational design of cytotoxic T-cell inhibitors. Nat Biotechnol 18, 984–988 (2000). https://doi.org/10.1038/79487

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