MHC Ib molecule Qa-1 presents Mycobacterium tuberculosis peptide antigens to CD8+ T cells and contributes to protection against infection

• Published in: PLoS pathogens Vol. 13; no. 5; p. e1006384
• Main Authors: Bian, Yao, Shang, Shaobin, Siddiqui, Sarah, Zhao, Jie, Joosten, Simone A, Ottenhoff, Tom H M, Cantor, Harvey, Wang, Chyung-Ru
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-05-2017; Public Library of Science (PLoS)
• Subjects: Aerosols; Animal models; Animals; Antigen Presentation - immunology; Antigens; Antigens, Bacterial - immunology; Apoptosis; Bacteria; Biology and Life Sciences; Biotechnology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell death; Cell lines; Cell surface; CTLA-4 protein; Cytokines; Cytokines - immunology; Cytotoxicity; Effector cells; Fas antigen; Histocompatibility antigen HLA; Histocompatibility Antigens Class I - immunology; Homology; Humans; Immune response; Immune system; Immunity; Immunology; Infections; Infectious diseases; Inflammation; KLRG1 protein; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - immunology; Major histocompatibility complex; Markers; Medicine; Medicine and Health Sciences; Mice; Microorganisms; Mortality; Mycobacterium tuberculosis - immunology; Patients; PD-1 protein; Peptides; Public health; Regulation; Research and Analysis Methods; Surface markers; T cell receptors; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Regulatory - immunology; Tuberculosis; Tuberculosis - immunology; Tuberculosis - microbiology; Vaccines; Viral infections; United States > US; Illinois; Chicago Illinois
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1006384

A number of nonclassical MHC Ib molecules recognizing distinct microbial antigens have been implicated in the immune response to Mycobacterium tuberculosis (Mtb). HLA-E has been identified to present numerous Mtb peptides to CD8+ T cells, with multiple HLA-E-restricted cytotoxic T lymphocyte (CTL) and regulatory T cell lines isolated from patients with active and latent tuberculosis (TB). In other disease models, HLA-E and its mouse homolog Qa-1 can act as antigen presenting molecules as well as regulators of the immune response. However, it is unclear what precise role(s) HLA-E/Qa-1 play in the immune response to Mtb. In this study, we found that murine Qa-1 can bind and present Mtb peptide antigens to CD8+ T effector cells during aerosol Mtb infection. Further, mice lacking Qa-1 (Qa-1-/-) were more susceptible to high-dose Mtb infection compared to wild-type controls, with higher bacterial burdens and increased mortality. The increased susceptibility of Qa-1-/- mice was associated with dysregulated T cells that were more activated and produced higher levels of pro-inflammatory cytokines. T cells from Qa-1-/- mice also had increased expression of inhibitory and apoptosis-associated cell surface markers such as CD94/NKG2A, KLRG1, PD-1, Fas-L, and CTLA-4. As such, they were more prone to cell death and had decreased capacity in promoting the killing of Mtb in infected macrophages. Lastly, comparing the immune responses of Qa-1 mutant knock-in mice deficient in either Qa-1-restricted CD8+ Tregs (Qa-1 D227K) or the inhibitory Qa-1-CD94/NKG2A interaction (Qa-1 R72A) with Qa-1-/- and wild-type controls indicated that both of these Qa-1-mediated mechanisms were involved in suppression of the immune response in Mtb infection. Our findings reveal that Qa-1 participates in the immune response to Mtb infection by presenting peptide antigens as well as regulating immune responses, resulting in more effective anti-Mtb immunity.