Abstract
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.
Highlights
As the causative agent of tuberculosis (TB), Mycobacterium tuberculosis (Mtb) is a continuing global public health concern that kills approximately 2 million people annually, with an estimated one-third of the world’s population infected with Mtb [1]
We found that Qa-1 can present Mtb peptides to activate CD8+ T effector cells during aerosol Mtb infection
Using mice expressing different mutant forms of Qa-1, we showed that Qa-1 can regulate immune responses against Mtb through the interaction with inhibitory CD94/NKG2A receptors as well as the activation of regulatory CD8+ T cells
Summary
As the causative agent of tuberculosis (TB), Mycobacterium tuberculosis (Mtb) is a continuing global public health concern that kills approximately 2 million people annually, with an estimated one-third of the world’s population infected with Mtb [1]. Mtb-specific CD8+ T cells are potent producers of IFN-γ and TNF-α, cytokines crucial to anti-Mtb immunity [3, 4]. While current Mtb subunit vaccine development has primarily focused on CD4+ and MHC Ia-restricted CD8+ T cell responses [5], increasing evidence shows that non-conventional CD8+ T cells restricted by MHC Ib molecules can recognize distinct microbial antigens and contribute to protection against Mtb infection [6,7,8]. MHC Ib molecules CD1, MR1, Qa-1/HLA-E and Qa-2/HLA-G have been implicated in the host immune response against Mtb in mice and/or humans [6,7,8,9,10].
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