![]() The MAIT cell subset is an integral component of the human immune system ( 7), and they participate in immune responses to infection, both bacterial ( 8, 9) and viral ( 10– 13), with their primary effector output being the production of T helper (Th) 1 cytokines TNF and IFN-γ ( 14, 15). They are activated by microbial metabolites produced during vitamin B2 and B9 biosynthesis presented via MR1 ( 3, 4), or in a TCR-independent manner by cytokines IL-12 and IL-18 ( 5, 6). Mucosal-associated invariant T (MAIT) cells are an unconventional T cell population that is restricted by the MHC class I–like molecule, MR1 ( 1, 2). ![]() These results demonstrate that the TCR-dependent effector response of MAIT cells is epigenetically regulated and dependent on the availability of metabolic cofactors. However, addition of the KDM6B cofactor α-ketoglutarate greatly enhanced MAIT cell effector capacity to TCR-dependent stimulation in a partially KDM6B-dependent manner. Addition of a KDM6B inhibitor did not alter MAIT cell effector function to Ag or cytokine stimulation. Global gene transcription analysis revealed that the MAIT cell effector capacity produced in response to TCR stimulation is associated with increased expression of the epigenetic regulator lysine demethylase 6B (KDM6B). We demonstrate the heterogenous nature of MAIT cell effector capacity and that the ability to produce an effector response is not directly attributable to TCR clonotype or coreceptor expression. To address this, we have taken a systematic approach to examine human MAIT cell effector capacity across healthy individuals in response to ligand and cytokine stimulation. It is unclear what factors control MAIT cell effector capacity, whether it is fixed or can be modified and if this differs based on whether activation is TCR dependent or independent. Yet, there is heterogeneity in MAIT cell effector response. Because of this reactivity and surface expression of CD45RO +, CD45RA −, and CD127 +, they are described as effector memory cells. Mucosal-associated invariant T (MAIT) cells are an innate-like population of unconventional T cells that respond rapidly to microbial metabolite Ags or cytokine stimulation.
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