HLA-E–restricted CD8+ T Lymphocytes Efficiently Control <i>Mycobacterium tuberculosis</i> and HIV-1 Coinfection

Abstract We investigated the contribution of human leukocyte antigen A2 (HLA-A2) and HLA-E–restricted CD8+ T cells in patients with Mycobacterium tuberculosis and human immunodeficiency virus 1 (HIV-1) coinfection. 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, owing to the inability of the virus to downmodulate their expression. Therefore, antigen-specific HLA-E–restricted CD8+ T cells could play a protective role in Mycobacterium tuberculosis and HIV-1 coinfection. 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 were evaluated ex vivo in patients with active tuberculosis and concomitant HIV-1 infection. HIV-1 and Mycobacterium tuberculosis coinfection 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 coinfection, as measured by tetramer staining, but displayed a terminally differentiated and exhausted phenotype that was rescued in vitro by anti–PD-1 (programmed cell death protein 1) monoclonal antibody. Together, these results indicate that HLA-E–restricted and Mycobacterium tuberculosis–specific CD8+ T cells in patients with Mycobacterium tuberculosis/HIV-1 coinfection have an exhausted phenotype and fail to expand in vitro in response to antigen stimulation, which can be restored by blocking the PD-1 pathway using the specific monoclonal antibody nivolumab.