HLA-E-restricted CD8 + T Lymphocytes Efficiently Control Mycobacterium tuberculosis and HIV-1 Coinfection

Am J Respir Cell Mol Biol. 2020 Apr;62(4):430-439. doi: 10.1165/rcmb.2019-0261OC.

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.

Keywords: CD8+ T lymphocytes; HIV-1; HLA-E; Mycobacterium tuberculosis; tetramers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antigens, Bacterial / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • Coinfection / immunology*
  • Down-Regulation / immunology
  • Female
  • HIV Infections / immunology*
  • HIV-1 / immunology*
  • HLA-A2 Antigen / immunology*
  • Histocompatibility Antigens Class I / immunology*
  • Humans
  • Lymphocyte Activation / immunology
  • Lymphocyte Count / methods
  • Male
  • Middle Aged
  • Mycobacterium tuberculosis / immunology*
  • Tuberculosis / immunology*

Substances

  • Antigens, Bacterial
  • HLA-A2 Antigen
  • HLA-E antigen
  • Histocompatibility Antigens Class I