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.

Keywords: CD56; MHC class I-related; antibacterial immunity; cytokines; microbial immunity; mucosa-associated invariant T cells; mucosal immunology.

Figure 1

Summary of the mucosa-associated invariant T (MAIT) cell, antigen-presenting cell (APC), and microbial factors that may influence MAIT cell antimicrobial responses. The MAIT cell TCR β-chain and the expression of CD56 and of co-stimulatory and co-inhibitory receptors influence their responses to microbial stimuli. Microbes with distinct pathogen-associated molecular pattern (PAMP) repertoires and differential expression of the riboflavin operon differently activate APCs and influence the type and amount of MAIT cell agonists or folic acid derivative/non-stimulatory compounds that are presented to MAIT cells, respectively. APCs differ in the amount of MHC class I-related–antigen complexes presented to MAIT cells, the type and amount of innate cytokines produced, as well as the panel of co-inhibitory and co-activating molecules expressed. The combination of all these factors influences downstream MAIT cell responses, both cytokine production and cytolytic capacity, in different tissues, such as peripheral blood and the female genital mucosa.