MHC-PEPTIDE BINDING - DIMERS OF CYSTEINE-CONTAINING NONAPEPTIDES BINDWITH HIGH-AFFINITY TO HLA-A2.1 CLASS-I MOLECULES

Small peptides, 8-10 aminoacids long, derived from degradation of cyto plasmic proteins by a proteasome-proteinase complex, are usually prese nted and recognized by CD8(+) cytolytic T lymphocytes (CTLs) associate d with major histocompatibility complex (MHC) class I molecules. Recen tly synthetic peptides were used for the in vitro induction of tumor-s pecific CTLs, offering another strategy in the study of the immune-res ponse repertoire and providing a new tool in cancer vaccination and im munotherapy. Peptides derived from otherwise normal proteins, overexpr essed in many tumors as products of the protooncogene, may represent a target for an immune response. This is the case of HER-2/neu gene (al so known as ErbB-2), encoding a cysteine-rich glycoprotein transmembra ne receptor with tyrosine kinase activity (gp185neu). Recent data, dem onstrating that HLA-A2.1-related peptides are able to stimulate in vit ro CD8(+) lymphocytes, prompted us to study the binding to HLA-A2.1 mo lecules of several gp185 synthetic peptides containing a cystein resid ue and to define the relevance of this amino acid residue in the reduc ed or oxidated form of the sulfhydryl group. We found that monomers an d their homodimers, linked by a disulfide bridge, bind to HLA-A2.1 mol ecules with overlapping affinity. These results suggest that additiona l amino acids of the nonapeptide do not prevent the binding and the HL A refolding through chemical or sterical interactions. This might be o f particular relevance for the in vivo processing of cysteine-rich pro teins. Because ErbB-2 molecules, as tumor-differentiation antigens in melanoma, are cysteine-rich molecules, it may be relevant to evaluate the possible role of the cystine residues interacting with the T-cell receptor. The recognition of these heterodimers by CD8(+) lymphocytes will require functional in vivo studies.