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Mucosa-associated Invariant T (MAIT) cells are an evolutionarily conserved innate-like T cell subset that recognizes antigens presented by MR1 molecules. These antigens include vitamin B derivatives shared by many potentially pathogenic microbes, including Mycobacterium tuberculosis and Candida albicans. It was recently discovered that MAIT cells decay numerically and functionally in HIV-1 infection, and that they fail to recover despite several years of effective suppression of viral replication by antiretroviral therapy (ART). Here, we briefly discuss the roles of MAIT cells and their loss in HIV immunopathogenesis. We furthermore propose that the persistence of MAIT cell loss on ART needs to be taken into account when assessing the immunological response to treatment, and when treatment should commence. The importance of this T cell subset in HIV-1 infection needs further study, and interventions to restore the MAIT cell compartment should be considered.

Antimicrobial resistance is a serious threat to global public health as antibiotics are losing effectiveness due to rapid development of resistance. The human immune system facilitates control and clearance of resistant bacterial populations during the course of antimicrobial therapy. Here we review current knowledge of mucosa-associated invariant T (MAIT) cells, an arm of the immune system on the border between innate and adaptive, and their critical place in human antibacterial immunity. We propose that MAIT cells play important roles against antimicrobial-resistant infections through their capacity to directly clear multidrug-resistant bacteria and overcome mechanisms of antimicrobial resistance. Finally, we discuss outstanding questions pertinent to the possible advancement of host-directed therapy as an alternative intervention strategy for antimicrobial-resistant bacterial infections. Host immunity is an important factor in clearing antibiotic-resistant bacterial infections that is often neglected. Understanding host immunity can provide novel insights for alternative intervention strategies against antimicrobial resistance. Mucosa-associated invariant T (MAIT) cells are key players in human antibacterial immunity. These highly abundant unconventional T cells recognise by-products from bacterial vitamin B 2 biosynthesis, and mediate bacterial control through direct killing and orchestrating downstream immune responses. MAIT cells have the capacity to control drug-resistant bacteria and overcome resistance. This suggests that MAIT cells may participate in the clearance of bacteria that acquire resistance during antibiotic therapy and may provide protection against infections by resistant bacteria. Enhancing MAIT cell properties may be a viable prophylaxis and alternative treatment strategy in vulnerable populations. [ABSTRACT FROM AUTHOR]

Mucosa‐associated invariant T (MAIT) cells are unconventional T lymphocytes defined by their innate‐like characteristics and broad antimicrobial responsiveness. Whether MAIT cells are part of the tissue‐resident defense in the oral mucosal barrier is unknown. Here, we found MAIT cells present in the buccal mucosa, with a tendency to cluster near the basement membrane, and located in both epithelium and the underlying connective tissue. Overall MAIT cell levels were similar in the mucosa compared to peripheral blood, in contrast to conventional T cells that showed an altered representation of CD4+ and CD8+ subsets. The major mucosal MAIT cell subset displayed a tissue‐resident and activated profile with high expression of CD69, CD103, HLA‐DR, and PD‐1, as well as a skewed subset distribution with higher representation of CD4–/CD8– double‐negative cells and CD8αα+ cells. Interestingly, tissue‐resident MAIT cells had a specialized polyfunctional response profile with higher IL‐17 levels, as assessed by polyclonal stimulus and compared to tissue nonresident and circulating populations. Furthermore, resident buccal MAIT cells were low in perforin. Together, these data indicate that MAIT cells form a part of the oral mucosal T cell compartment, where they exhibit a tissue‐resident‐activated profile biased toward IL‐17 production. MAIT cells are part of the human buccal mucosal immune defenses. Buccal MAIT cells are enriched in the CD4–CD8– phenotypic subset and can be further sub‐divided based on tissue residency markers CD103 and CD69. The buccal MAIT cells have distinct polyfunctional response profiles with high IL‐17 and low IFN‐γ production. [ABSTRACT FROM AUTHOR]

Mucosa-associated invariant T (MAIT) cells are unconventional innate-like T cells that recognize microbial riboflavin metabolites presented by the MHC class I-like protein MR1. Human MAIT cells predominantly express the CD8α coreceptor (CD8+), with a smaller subset lacking both CD4 and CD8 (double-negative, DN). However, it is unclear if these two MAIT cell subpopulations distinguished by CD8α represent functionally distinct subsets. Here, we show that the two MAIT cell subsets express divergent transcriptional programs and distinct patterns of classic T cell transcription factors. Furthermore, CD8+ MAIT cells have higher levels of receptors for IL-12 and IL-18, as well as of the activating receptors CD2, CD9, and NKG2D, and display superior functionality following stimulation with riboflavin-autotrophic as well as riboflavin-auxotrophic bacterial strains. DN MAIT cells display higher RORγt/T-bet ratio, and express less IFN-γ and more IL-17. Furthermore, the DN subset displays enrichment of an apoptosis gene signature and higher propensity for activation-induced apoptosis. During development in human fetal tissues, DN MAIT cells are more mature and accumulate over gestational time with reciprocal contraction of the CD8+ subset. Analysis of the T cell receptor repertoire reveals higher diversity in CD8+ MAIT cells than in DN MAIT cells. Finally, chronic T cell receptor stimulation of CD8+ MAIT cells in an in vitro culture system supports the accumulation and maintenance of the DN subpopulation. These findings define human CD8+ and DN MAIT cells as functionally distinct subsets and indicate a derivative developmental relationship. [ABSTRACT FROM AUTHOR]

Mucosa-associated invariant T (MAIT) cells are a large innate-like T-cell subset in humans defined by invariant TCR Vα7.2 use and expression of CD161. MAIT cells recognize microbial riboflavin metabolites of bacterial or fungal origin presented by the monomorphic MR1 molecule. The extraordinary level of evolutionary conservation of MR1 and the limited known diversity of riboflavin metabolite antigens have suggested that MAIT cells are relatively homogeneous and uniform in responses against diverse microbes carrying the riboflavin biosynthesis pathway. The ability of MAIT cells to exhibit microbe-specific functional specialization has not been thoroughly investigated. Here, we found that MAIT cell responses against Escherichia coli and Candida albicans displayed microbe-specific polyfunctional response profiles, antigen sensitivity and response magnitudes. MAIT cell effector responses against E. coli and C. albicans displayed differential MR1 dependency and TCR β-chain bias, consistent with possible divergent antigen subspecificities between these bacterial and fungal organisms. Finally, although the MAIT cell immunoproteome was overall relatively homogenous and consistent with an effector memory-like profile, it still revealed diversity in a set of natural killer cell-associated receptors. Among these, CD56, CD84 and CD94 defined a subset with higher expression of the transcription factors promyelocytic leukemia zinc finger (PLZF), eomesodermin and T-bet and enhanced capacity to respond to IL-12 and IL-18 stimulation. Thus, the conserved and innate-like MAIT cells harbor multiple layers of functional heterogeneity as they respond to bacterial or fungal organisms or innate cytokines and adapt their antimicrobial response patterns in a stimulus-specific manner. [ABSTRACT FROM AUTHOR]