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Mucosal-Associated Invariant T Cell Effector Function Is an Intrinsic Cell Property That Can Be Augmented by the Metabolic Cofactor α-Ketoglutarate

ABSTRACT: Mucosal-associated invariant T (MAIT) cells are an innate-like population of unconventional T cells that respond rapidly to vitamin B metabolite antigens or cytokine stimulation. Due to this reactivity and surface expression of CD45RO+, CD45RA−, CD127+, they are described as effector memory cells. Yet, there is a lack of uniformity in the MAIT cell effector response. it is unclear what factors contribute to setting MAIT cells effector capacity and whether it is fixed or can be modified. To address this, we have taken a systematic approach to examine MAIT cells effector capacity across healthy individuals in response to ligand and cytokine stimulation. We demonstrate the heterogenous nature of MAIT cells effector capacity, and that the ability to produce an effector response was not directly attributable to TCR clonotype or coreceptor expression. Global gene transcription analysis revealed that the MAIT cells effector capacity produced in response to TCR stimulation was associated with the expression of the epigenetic regulator lysine demethylase 6B (KDM6B). Addition of a KDM6B inhibitor does not alter MAIT cell effector function. However, addition of the KDM6B cofactor α-ketoglutarate greatly enhanced MAIT cells effector capacity in a KDM6B-dependent manner. These results demonstrate that the MAIT cells effector response is epigenetically regulated and can be targeted for enhancement.

ORGANISM(S): Homo sapiens

PROVIDER: GSE164740 | GEO | 2021/01/14

REPOSITORIES: GEO

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