Inflammatory signals control human MAIT cell effector function

Abstract

Abstract Mucosal-associated invariant T (MAIT) cells recognize bacterial metabolites presented on MR1 via their semi-invariant T cell receptor (TCR). MAIT cells are a potent effector population located in tissues that are constantly exposed to the microbiome. This raises the question how MAIT cell activation is regulated to avoid unwanted responses to microbiome-derived metabolites. To address this we dissected the MAIT cell response to TCR- and cytokine-mediated signals. We found that stimulating the MAIT TCR in the absence of inflammatory cytokines was not sufficient to induce effector function such as granzyme B and interferon-g expression. Inflammatory signals acting directly on MAIT cells were absolutely necessary to allow for TCR-mediated acquisition of effector function. Importantly, MAIT cells are not generally hyporesponsive to TCR-mediated signals as TCR stimulation in the absence of inflammation elicited a distinct chemokine response. Single-cell gene expression analysis of MAIT cells isolated from healthy human mucosal tissue revealed increased expression of inflammatory genes compared to their counterparts in the blood, indicating that provided the proper signals mucosal MAIT cells are poised to respond rapidly to infection. Importantly, MAIT cells in the mucosa do not produce inflammatory cytokines directly ex-vivo, despite expressing higher levels of inflammatory transcript. We propose a novel model in which the strict dependence of TCR-mediated signals on pro-inflammatory cytokines to induce effector function represents a MAIT cell-intrinsic mechanism to prevent unwanted responses to commensal bacteria-derived bacterial metabolites, while allowing potent effector responses following infection.