HLA-DERIVED PEPTIDES WHICH INHIBIT T-CELL FUNCTION BIND TO MEMBERS OFTHE HEAT-SHOCK-PROTEIN-70 FAMILY

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 conserve d region of the alpha 1 helix of HLA class I molecules that overlaps t he ''public epitope'' Bw4/Bw6. These HLA-derived peptides exhibit inhi bitory effects on T lymphocytes and have beneficial effects on the sur vival of allogeneic organ transplants in mice and rats. Peptides corre sponding to the Bw4a epitope appear most potent as they inhibit the di fferentiation of T cell precursors into mature cytotoxic T lymphocytes (CTL) and target cell lysis by established CTL lines and clones. To e lucidate the mechanism through which these peptides mediate their inhi bitory effect on T lymphocytes, peptide binding proteins were isolated from T cell lysates. We show that the inhibitory Bw4a peptide binds t wo members of the heat-shock protein (HSP) 70 family, constitutively e xpressed HSC70 and heat-inducible HSP70. Peptide binding to HSC/HSP70 is sequence specific and follows the rules defined by the HSC70 bindin g motif. Most intriguing, however, is the strict correlation of peptid e binding to HSC/HSP70 and the functional effects such that only inhib itory 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 interactin g with HSPs. In contrast to numerous reports of HSP70 expression at th e 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' immunomodulatory eff ects are not mediated through a signaling event initiated by interacti on of peptide with surface HSP, but favor a model similar to the actio n of other immunomodulatory compounds, FK506 and cyclosporin A, with a role for HSC/HSP70 similar to that for immunophilins, FKBPs and CyP40 .