Factors Influencing Functional Heterogeneity in Human Mucosa-Associated Invariant T Cells

Abstract

Mucosa-associated invariant T (MAIT) cells are unconventional innate-like T cells that recognize microbial riboflavin metabolites presented by the monomorphic MHC class I-related (MR1) molecule. Despite the high level of evolutionary conservation of MR1 and the limited diversity of known antigens, human MAIT cells and their responses may not be as homogeneous as previously thought. Here, we review recent findings indicating that MAIT cells display microbe-specific response patterns with multiple layers of heterogeneity. The natural killer cell receptor CD56 marks a MAIT cell subset with distinct response profile, and the T cell receptor β-chain diversity influences responsiveness at the single cell level. The MAIT cell tissue localization also influences their response profiles with higher IL-17 in tissue-resident MAIT cells. Furthermore, there is emerging evidence that the type of antigen-presenting cells, and innate cytokines produced by such cells, influence the quality of the ensuing MAIT cell response. On the microbial side, the expression patterns of MR1-presented antigenic and non-antigenic compounds, expression of other bioactive microbial products, and of innate pattern recognition ligands all influence downstream MAIT cell responses. These recent findings deepen our understanding of MAIT cell functional diversity and adaptation to the type and location of microbial challenge.

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“…MAIT cells have a semi-invariant TCR of a Vα7.2 segment with either Jα12, 20 or 33, and a limited β chain diversity. Vitamin B2 metabolites presented by MR1 are the classical activating ligand of MAIT cells [ 148 ], but they can also be activated in an MR1-independent and/or cytokine-driven manner in response to viral infection [ 149 ]. These characteristics allow MAIT cells to respond to a broad range of pathogens in a rapid, innate-like manner.…”

“…These characteristics allow MAIT cells to respond to a broad range of pathogens in a rapid, innate-like manner. When activated, MAIT cells release a variety of cytokines, in particular TNF and IFNγ, as well as IL-17 and IL-22 for MAIT cells residing within tissues [ 148 ].…”

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“…MAIT cells belong to the class of innate immune T cells and were first described in 1993 in human blood. The name stems from the abundance of these cells at mucosal and inner barriers, that is, the lamina propria of the gut and liver 15 16. This cellular subset is characterised by its dependence on a monomorphic MHC Class I–related protein called MR1 for its selection and activation.…”

“…On MR1 activation, MAIT cells produce inflammatory cytokines with a mixed Th1/Th17-like response. Indeed, MAIT cells have the capacity to produce IFN-γ, TNF-α, IL-2, IL-17A and IL-22 15. MAIT cells are primarily located at mucosal surfaces and in the blood, and they represent around 6% to 10% of circulating CD3 + T cells.…”

“…The gating strategy that was used in the different studies to analysed MAIT cells by flow cytometry may also explain the heterogeneity of these results. Indeed, several factors may influence MAIT cell frequency and function: they decrease with age, are higher in obese subjects and are reduced with smoking habits 15–17. Conversely, gender does not affect MAIT cells 15.…”