Cross-reactive epitopes and HLA-restriction elements in human T cell recognition of the Mycobacterium leprae 18-kD heat shock protein

We have previously demonstrated that the Mycobacterium leprae 18-kD heat sh ock protein (HSP18) is represented among the antigenic targets of human T c ell responses induced by M. leprae immunization and that the peptide 38-50 serves as an immunodominant epitope recognized by CD4(+) T cell clones. By using peripheral blood mononuclear cells and T cell lines from the same don or group, we have in this study shown that the M. leprae HSP18 and peptide 38-50 were recognized by memory T cells 8 years after immunization with M. leprae. The finding that M. bovis BCG-induced T cell lines responded to M. leprae HSP18, but not to the peptide 38-50, suggested the existence of addi tional T cell epitopes of a cross-reactive nature. Consistent with this, te sting of the T cell lines for proliferative responses to the complete HSP18 molecule, truncated HSP18 (amino acid (aa) residues 38-148) and overlappin g synthetic peptides, made it possible to identify two cross-reactive epito pe regions defined by aa residues 1-38 and 41-55. While peptide 38-50-react ive T cell clones showed limited cross-reactivity by responding to M. lepra e, M. avium and M. scrofulaceum, the T cell lines specific to the epitopes 1-38 and 41-55 were broadly cross-reactive, as demonstrated by their respon se to M. leprae, M. tuberculosis complex, M. avium and other mycobacteria. MHC restriction analysis of the HSP18-responding T cell lines showed that t he epitopes 1-38 and 38-50 were presented by one of the two HLA-DR molecule s expressed from self HLA-DRB1 genes, whereas the epitope 41-55 was recogni zed in the presence of autologous as well as HLA-DR and HLA-DQ mismatched a llogeneic antigen-presenting cells. The results obtained in this study made it possible to identify cross-reactive T cell epitopes of the M. leprae HS P18, and provide an explanation for T cell recognition of this antigen in i ndividuals infected with species of the M. tuberculosis complex or environm ental mycobacteria.