Mucosal-Associated Invariant T Cell Effector Function Is an Intrinsic Cell Property That Can Be Augmented by the Metabolic Cofactor α-Ketoglutarate
Mucosal-Associated Invariant T Cell Effector Function Is an Intrinsic Cell Property That Can Be Augmented by the Metabolic Cofactor α-Ketoglutarate
复制标题
DOI：
10.4049/jimmunol.2001048
复制
发表时间：
2021-04-01
影响因子：
4.4
通讯作者：
Rossjohn, Jamie
中科院分区：
文献类型：
--
作者：
Howson, Lauren J.;Li, Jasmine;Rossjohn, Jamie
粘膜相关不变T（MAIT）细胞是一种对微生物代谢产物Ag或细胞因子刺激快速响应的非常规T细胞的先天样群体。由于这种反应性和CD 45 RO（+）、CD 45 RA（-）和CD 127（+）的表面表达，它们被描述为效应记忆细胞。然而，MAIT细胞效应子应答存在异质性。目前还不清楚是什么因素控制MAIT细胞效应子能力，它是固定的还是可以被修饰的，以及这是否基于活化是TCR依赖性的还是独立的而不同。为了解决这个问题，我们已经采取了一种系统的方法来检查人类MAIT细胞效应器的能力在健康个体响应配体和细胞因子刺激。我们证明了MAIT细胞效应子能力的异质性，并且产生效应子应答的能力不直接归因于TCR克隆型或辅助受体表达。全局基因转录分析显示，响应于TCR刺激产生的MAIT细胞效应子能力与表观遗传调节因子赖氨酸脱甲基酶6 B（KDM 6 B）的表达增加相关。KDM 6 B抑制剂的添加没有改变MAIT细胞对Ag或细胞因子刺激的效应功能。然而，KDM 6 B辅因子α-酮戊二酸的添加以部分KDM 6 B依赖性方式极大地增强了MAIT细胞效应子对TCR依赖性刺激的能力。这些结果表明，MAIT细胞的TCR依赖性效应子应答受表观遗传学调节，并依赖于代谢辅因子的可用性。
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 alpha-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.