Human T cells recognize mycobacterial heat shock proteins in the context of multiple HLA-DR molecules: studies with healthy subjects vaccinated with Mycobacterium bovis BCG and Mycobacterium leprae

Abstract

Heat shock proteins (HSP) are considered to be important targets of the immune response to mycobacteria and, as such, relevant to subunit vaccine design. If HSP are major antigens in cell-mediated immunity, they should be recognized in the context of most of the HLA-DR molecules required for presentation of mycobacterial antigens to T cells. We tested peripheral blood mononuclear cells (PBMC) and T-cell lines from Mycobacterium leprae- and M. bovis BCG-vaccinated subjects for proliferation in response to the 18- and 65-kDa HSP of M. leprae, the 65-kDa HSP of M. bovis BCG, and the 70-kDa HSP of M. tuberculosis. Irrespective of HLA types, PBMC showing a strong response to M. leprae proliferated in response to mycobacterial HSP. HLA restriction analysis with T-cell lines showed that the M. leprae 18-kDa HSP was recognized in the context of HLA-DR4, HLA-Dw4, and HLA-DR1 molecules. The T-cell lines recognized the M. leprae 65-kDa HSP in the context of all of the HLA-DR molecules expressed by autologous antigen-presenting cells, i.e., HLA-DR1, HLA-DR2, HLA-DR5, HLA-DR7, and importantly HLA-DR4 (HLA-Dw4 and HLA-Dw14), which is relevant to autoimmunity. The M. tuberculosis 70-kDa antigen was also presented to the T-cell lines by HLA-DR1, HLA-DR2, HLA-DR5, and HLA-DR7 molecules. In addition, this HSP was recognized in the context of the HLA-DRw53 molecule, which is frequently expressed in many regions where leprosy is endemic. The T-cell lines proliferating in response to a given HSP lysed autologous monocytes-macrophages pulsed with that HSP. The results demonstrate that PBMC from individuals immunized with M. leprae respond to mycobacterial HSP and that these HSP are presented to T cells by multiple HLA-DR molecules, a prerequisite for their application in the next generation of subunit vaccines.