HLA-E-Restricted CD8+ T Lymphocytes Efficiently Control Mycobacterium tuberculosis and HIV-1 Co-Infection

Abstract

RATIONALE: We have investigated the contribution of HLA-A2 and HLA-E-restricted CD8+ T cells in patients with Mycobacterium tuberculosis and HIV-1 co-infection. OBJECTIVE: HIV-1 downregulates HLA-A, -B and -C molecules in infected cells thus influencing recognition by HLA class I-restricted CD8+ T cells but not by HLA-E restricted CD8+ T cells due to the inability of the virus to downmodulate their expression. Therefore antigen-specific HLA-E-restricted CD8+ T cells could play a protective response in Mycobacterium tuberculosis and HIV-1 co-infection. METHODS: HLA-E- and HLA-A2-restricted Mycobacterium tuberculosis-specific CD8+ T cells were tested in vitro for cytotoxic and microbicidal activities and their frequencies and phenotypes evaluated ex vivo in patients with active tuberculosis and concomitant HIV-1 infection. MEASUREMENTS AND MAIN RESULTS: HIV-1 and Mycobacterium tuberculosis co-infection caused downmodulation of HLA-A2 expression in human monocyte-derived, macrophages associated with resistance to lysis by HLA-A2-restricted CD8+ T cells and failure to restrict the growth of intracellular Mycobacterium tuberculosis. Conversely, HLA-E surface expression and HLA-E-restricted cytolytic and microbicidal CD8 responses were not affected. HLA-E-restricted and Mycobacterium tuberculosis-specific CD8+ T cells were expanded in the circulation of patients with Mycobacterium tuberculosis/HIV-1 co-infection, as measured by tetramer staining, but displayed a terminally-differentiated and exhausted phenotype which was rescued in vitro by anti-programmed death-1 monoclonal antibody. CONCLUSIONS: HLA-E-restricted and Mycobacterium tuberculosis-specific CD8+ T cells in patients with Mycobacterium tuberculosis/HIV-1 co-infection have an exhausted phenotype and fail to expand in vitro in response to antigen stimulation, which can be restored by blocking programmed death-1 pathway using the specific monoclonal antibody Nivolumab.