MAIT Cells in Barrier Tissues: Lessons from Immediate Neighbors

Abstract

Mucosal-associated invariant T (MAIT) cells are innate-like T cells present at considerable frequencies in human blood and barrier tissues, armed with an expanding array of effector functions in response to homeostatic perturbations. Analogous to other barrier immune cells, their phenotype and function is driven by crosstalk with host and dynamic environmental factors, most pertinently the microbiome. Given their distribution, they must function in diverse extracellular milieus. Tissue-specific and adapted functions of barrier immune cells are shaped by transcriptional programs and regulated through a blend of local cellular, inflammatory, physiological, and metabolic mediators unique to each microenvironment. This review compares the phenotype and function of MAIT cells with other barrier immune cells, highlighting potential areas for future exploration. Appreciation of MAIT cell biology within tissues is crucial to understanding their niche in health and disease.

Keywords: diet; metabolism; microbiome; microenvironment; mucosal immunology; mucosal-associated invariant T cells; tissue resident cells.

Figure 1

Summary of mucosal environmental factors which could influence immune responses directly and indirectly. Created with Biorender.com.

Figure 2

Potential regulation of the MAIT cell transcriptome and effector function by environmental cues. MAIT cells can be activated (A) independent of TCR-ligands by cytokines, or (B) through TCR-mediated recognition of microbial-derived riboflavin derivates presented by MR1. These signals can work both independently and synergistically to induce a spectrum of different effector programs. Cytokine-mediated MAIT activation results in the induction of a strong anti-microbial program (C), including the production of cytokines like IFNγ, IL-26 and members of the IL-17 family as well as pro-inflammatory chemokines like CXCL9 and CXCL10. These antimicrobial functions are further amplified with concurrent TCR signaling. TCR signals result in the induction of a homeostatic response (D), including cytokines associated with barrier maintenance (IL-22, IL-17), and proteins associated with tissue repair, such as the endoprotease furin. MAIT cells effector functions are controlled by the transcription factors PLZF, RoRγt, and Tbet. Importantly, while PLZF expression within MAITs is stable, expression of the homeostatic effector program is associated with increased expression of RoRγt and decreased expression of Tbet. Finally, TCR-mediated MAIT cell activation also leads to expression of HIF1A, another transcription factor associated with tissue repair. In addition to TCR-ligands and cytokines, several other factors have the potential to modulate MAIT cell activation. Bile acids and L-lactate were shown to generally reduce MAIT cell responses, while binding of Vitamin D to its receptor (VDR), the expression of which is upregulated in MAIT cells in response to TCR-signaling, has the potential to specifically inhibit the homeostatic response. In contrast, recognition of several other metabolites including AhR ligands, Vitamin A and lipids was associated with the expression of homeostatic effector molecules in other T cell populations and hence, could positively influence the expression of these molecules in MAIT cells as well. Similarly, short-chain fatty acids (SCFA), a product of bacterial metabolism, were shown to stimulate production of IL-22 and expansion of RORγt-expression lymphocytes in other immune cells, while reducing the antimicrobial function of MAIT cells, which could overall present a mechanism to preserve tissue homeostasis. Created with Biorender.com.