DR3-restricted T cells from different HLA-DR3-positive individuals recognize the same peptide (amino acids 2-12) of the mycobacterial 65-kDa heat-shock protein.

Studies in experimental animals have demonstrated that the T cell response to immunogenic proteins is limited to one or a few epitopes on such proteins and that the MHC haplotype of the responder is an important factor in determining which epitope is recognized (immune response gene effect). However, if and to what extent MHC genes control the immune response to pathogens in man is virtually unknown. We have studied the human T cell response to the mycobacterial 65-kDa heat-shock protein, a major immunogen of Mycobacterium leprae and M. tuberculosis, the causative agents of leprosy and tuberculosis, respectively, in relation to HLA-DR phenotype. In a large panel of short-term cultured polyclonal anti-mycobacterial T cell lines, from 45 different individuals representing all DR-restriction specificities, only DR1 and DR3-restricted T cell lines proliferated to the 65-kDa protein. The DR1-restricted T cell lines responded to three new epitopes on the mycobacterial 65-kDa protein, one of which is specific for the M. tuberculosis complex. Altogether nine T cell epitope-containing regions have now been mapped on the 65-kDa protein and the response to each of them was exclusively restricted via one HLA-DR allele. Most importantly, all six 65-kDa-responsive DR3-restricted T cell lines from different individuals recognized an epitope on the same peptide, representing amino acids 2-12 of the 65-kDa protein, that was previously mapped using DR3-restricted T cell clones. From these data we conclude that the human T cell response to both the whole mycobacterial 65-kDa heat-shock protein and to defined epitopes on this protein is controlled by HLA-DR genes. The mycobacterial 65-kDa protein has been implicated in the design of subunit vaccines against tuberculosis and leprosy as well as the induction of immunopathology. In both instances the Ir gene control of the T cell response to this protein may have to be taken into account.