HLA-derived peptides which inhibit T cell function bind to members of the heat-shock protein 70 family.
Open Access
- 1 February 1996
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 183 (2), 339-348
- https://doi.org/10.1084/jem.183.2.339
Abstract
Synthetic peptides corresponding to sequences of HLA class I molecules have inhibitory effects on T cell function. The peptides investigated in this study have sequences corresponding to the relatively conserved region of the alpha 1 helix of HLA class I molecules that overlaps the "public epitope" Bw4/Bw6. These HLA-derived peptides exhibit inhibitory effects on T lymphocytes and have beneficial effects on the survival of allogenic organ transplants in mice and rats. Peptides corresponding to the Bw4a epitope appear most potent as they inhibit the differentiation of T cell precursors into mature cytotoxic T lymphocytes (CTL) and target cell lysis by established CTL lines and clones. To elucidate the mechanism through which these peptides mediate their inhibitory effect on T lymphocytes, peptide binding proteins were isolated from T cell lysates. We show that the inhibitory Bw4a peptide binds two members of the heat-shock protein (HSP) 70 family, constitutively expressed HSC70 and heat-inducible HSP70. Peptide binding to HSC/HSP70 is sequence specific and follows the rules defined by the HSC70 binding motif. Most intriguing, however, is the strict correlation of peptide binding to HSC/HSP70 and the functional effects such that only inhibitory peptides bind to HSC70 and HSP70 whereas noninhibitory peptides do not bind. This correlation suggests that small molecular weight HLA-derived peptides may modulate T cell responses by directly interacting with HSPs. In contrast to numerous reports of HSP70 expression at the surface of antigen-presenting cells and some tumor cells, we find no evidence that HSC/HSP70 are expressed at the surface of the affected T cells. Therefore, we believe that the peptides' immunodulatory effects are not mediated through a signaling event initiated by interaction of peptide with surface HSP, but favor a model similar to the action of other immunomodulatory compounds, FK506 and cyclosporin A, with a role for HSC/HSP70 similar to that for immunophilins, FKBPs and CyP40.Keywords
This publication has 42 references indexed in Scilit:
- Protein folding in the cellNature, 1992
- Gorilla class I major histocompatibility complex alleles: comparison to human and chimpanzee class I.The Journal of Experimental Medicine, 1991
- Pretransplantation Blood Transfusion RevisitedNew England Journal of Medicine, 1991
- HLA-A2 peptides can regulate cytolysis by human allogeneic T lymphocytesNature, 1987
- Inhibition of alloreactive cytotoxic T lymphocytes by peptides from the α2 domain of HLA–A2Nature, 1987
- A mouse tumor-specific transplantation antigen is a heat shock-related protein.Proceedings of the National Academy of Sciences, 1986
- [29]Peptide mapping in gelsMethods in Enzymology, 1983
- Long-term human cytolytic T-cell lines allospecific for HLA-DR6 antigen are OKT4+.Proceedings of the National Academy of Sciences, 1982
- Improvement of Kidney-Graft Survival with Increased Numbers of Blood TransfusionsNew England Journal of Medicine, 1978
- No part may be reproduced by any process witnout written permission from the author(s) W4(4a) and W6(4b) in Diverse Human Populations. Demonstration of their Genetic Identity in Population and Segregation StudiesTissue Antigens, 1975