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

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.

Qa-1-Restricted CD8+ T Cells Can Compensate for the Absence of Conventional T Cells during Viral Infection

“…For example, MR1 presents vitamin B metabolites, which are unique to bacteria and yeast ( Kjer-Nielsen et al, 2012 ), and M3 binds N-formylated peptides of mitochondrial or prokaryotic origin ( Wang et al, 1991 ). We, therefore, focused on three non-classical molecules, namely, CD1d, Qa-1, and Qa-2, which have been shown to present pathogen-derived antigens ( Fischer et al, 2004 ; Bian et al, 2017 ; Swanson et al, 2008 ; Shang et al, 2016 ).…”

Detailed characterization of human Mycobacterium tuberculosis specific HLA‐E restricted CD8+ T cells

“…immunoregulatory activities of HLA-E restricted T cells was also found for the T-cell clones [14,22]. Not only the cytolytic effector functions but also the immunoregulatory properties of HLA-E restricted cells may be important in relation to protective immunity, by controlling pathogenic inflammation [23]. A negative consequence may be that immunoregulation contributes to pathogen persistence and chronic infection [11,30].…”

“…In subsequent work we demonstrated that HLA-Erestricted clonal CD8 + T cells were able to inhibit Mtb outgrowth in infected human macrophages [22]. Qa-1, the mouse homolog of HLA-E, can also present Mtb derived antigens during infection [23]. Mice that lack Qa-1, are more susceptible to Mtb infection and this increased susceptibility to progress to disease was due to dysregulated T-cell responses [23].…”

HLA-E: exploiting pathogen-host interactions for vaccine development

“…Their varying amino acid length implies that HLA-E has higher peptide binding plasticity than solely the VL9 peptide [75]. These non-canonical T cells contribute to the majority of T cells present during active Mtb infection [77], and overshadow T cells restricted by canonical HLA class Ia epitope presentation [78,79]. Mtb antigens presented by HLA-E to CD8 + T cells can induce either a cytotoxic or regulatory phenotype, consequently inhibiting Mtb pathogenesis and growth in infected macrophages [7,78].…”

“…These non-canonical T cells contribute to the majority of T cells present during active Mtb infection [77], and overshadow T cells restricted by canonical HLA class Ia epitope presentation [78,79]. Mtb antigens presented by HLA-E to CD8 + T cells can induce either a cytotoxic or regulatory phenotype, consequently inhibiting Mtb pathogenesis and growth in infected macrophages [7,78]. HLA-E : Mtb-restricted T cells from active TB infection express a type 2 cytokine profile with increased interleukin (IL)-4 and IL-10 production, and assist B cells with antibody and cytokine production to inhibit Mtb growth [65,76,77].…”