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

by Yao Bian, Shaobin Shang, Sarah Siddiqui, Jie Zhao, Simone A. Joosten, Tom H. M. Ottenhoff, Harvey Cantor, Chyung-Ru Wang

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⁺ T_regs (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.

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