Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia;
Infection and Immunity Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
J Immunol. 2021 Apr 1;206(7):1425-1435. doi: 10.4049/jimmunol.2001048. Epub 2021 Feb 17.
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. Because of this reactivity and surface expression of CD45RO, CD45RA, and CD127, they are described as effector memory cells. Yet, there is heterogeneity in MAIT cell effector response. 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. 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. 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. 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). Addition of a KDM6B inhibitor did not alter MAIT cell effector function to Ag or cytokine stimulation. However, addition of the KDM6B cofactor α-ketoglutarate greatly enhanced MAIT cell effector capacity to TCR-dependent stimulation in a partially KDM6B-dependent manner. These results demonstrate that the TCR-dependent effector response of MAIT cells is epigenetically regulated and dependent on the availability of metabolic cofactors.
黏膜相关不变 T（MAIT）细胞是一种先天样的非常规 T 细胞群体，对微生物代谢物 Ag 或细胞因子刺激迅速反应。由于这种反应性和 CD45RO、CD45RA 和 CD127 的表面表达，它们被描述为效应记忆细胞。然而，MAIT 细胞效应反应存在异质性。目前尚不清楚是什么因素控制 MAIT 细胞的效应能力，是固定的还是可以改变的，以及这种改变是否基于激活是否依赖 TCR。为了解决这个问题，我们采用系统的方法来检查健康个体对配体和细胞因子刺激的 MAIT 细胞效应能力。我们证明了 MAIT 细胞效应能力的异质性，并且产生效应反应的能力不能直接归因于 TCR 克隆型或共受体表达。全基因转录分析显示，TCR 刺激产生的 MAIT 细胞效应能力与表观遗传调节剂赖氨酸去甲基酶 6B（KDM6B）的表达增加有关。添加 KDM6B 抑制剂不会改变 MAIT 细胞对 Ag 或细胞因子刺激的效应功能。然而，添加 KDM6B 共因子 α-酮戊二酸以部分依赖 KDM6B 的方式极大地增强了 MAIT 细胞对 TCR 依赖性刺激的效应能力。这些结果表明，MAIT 细胞的 TCR 依赖性效应反应受表观遗传调控，并依赖于代谢共因子的可用性。
