HLA-restricted immune response to mycobacterial antigens: relevance to vaccine design

Identification of mycobacterial antigens that are recognized by CD4+ Th1 cells in HLA-nonrestricted manner or in association with multiple allelic products is required to develop universally effective vaccines against mycobacterial diseases. Our studies in this direction have shown that several recombinant mycobacterial antigens of cytosolic and culture filtrate origin are recognized by CD4+ Th1 cells. Mapping of T cell epitopes with overlapping synthetic peptides covering the entire sequence of these antigens identified peptide sequences stimulatory for Th1 cells. HLA-restriction analysis showed that in addition to HLA-DRB1 products (serologically defined HLA-DR1 to HLA-DR10), the HLA molecules encoded by HLA-DRB3 (HLA-DR52) and HLA-DRB4 (HLA-DR53) are important in presentation of mycobacterial antigens and epitopes to T cells. Depending on the T cell donor, the presentation of a given antigen or peptide could be restricted by HLA-DRB1, HLA-DRB3, and/or HLA-DRB4 products. In addition, stimulation of Th1 cells by some antigens and peptides in the presence of autologous and HLA-DR mismatched allogeneic APC suggested promiscuous presentation. These results taken together suggest that from HLA-restriction perspective, several mycobacterial antigens qualify as candidates for subunit or recombinant vaccine design against mycobacterial diseases.