Th1 and T17 activation with and without CB839 treatment. Th1 and T17 activation with and without CB839 treatment

Activated T cells differentiate into functional subsets which require distinct metabolic programs. Glutaminase (GLS) converts glutamine to glutamate to provide substrate for the tricarboxylic acid cycle and epigenetic reactions and here we identify a key role for GLS in T cell activation and specification. Though GLS-deficiency diminished T cell activation, proliferation and impaired differentiation of Th17 cells, loss of GLS also increased Tbet and Interferon-γ expression and CD4 Th1 and CD8 CTL effector cell differentiation. These changes were mediated by differentially altered gene expression and chromatin accessibility, leading to increased sensitivity of Th1 cells to IL-2 mediated mTORC1 signaling. In vivo, GLS-null T cells failed to drive a Th17-mediated Graft-vs-Host Disease model. Transient inhibition of GLS, however, increased Th1 and CTL T cell numbers in viral and chimeric antigen receptor models. Glutamine metabolism thus has distinct roles to promote Th17 but constrain Th1 and CTL effector cell differentiation. Overall design: Cells were treated with glutaminase1 inhibitor or vehicle

活化T细胞可分化为功能各异的亚群，该过程依赖于特异性的代谢程序。谷氨酰胺酶（Glutaminase, GLS）可将谷氨酰胺转化为谷氨酸，为三羧酸循环及表观遗传反应提供底物；本研究明确了GLS在T细胞活化与特化过程中的关键作用。尽管GLS缺失会削弱T细胞的活化、增殖能力，并损害辅助性T细胞17（Th17）的分化，但GLS的缺失同时可上调T-bet与干扰素-γ（Interferon-γ）的表达，促进CD4阳性Th1细胞与CD8阳性细胞毒性T淋巴细胞（CTL）的效应细胞分化。上述变化由基因表达与染色质可及性的差异性改变所介导，最终使得Th1细胞对白细胞介素2（IL-2）介导的雷帕霉素靶蛋白复合物1（mTORC1）信号通路的敏感性增强。在体内实验中，GLS敲除的T细胞无法诱导Th17介导的移植物抗宿主病（Graft-vs-Host Disease, GVHD）模型的发生。然而，对GLS进行暂时性抑制，可在病毒感染及嵌合抗原受体（chimeric antigen receptor, CAR）模型中增加Th1细胞与CTL的数量。由此可见，谷氨酰胺代谢具有双重功能：既可促进Th17细胞分化，亦可抑制Th1细胞与CTL效应细胞的分化。实验设计概述：使用谷氨酰胺酶1抑制剂或空白载体对照处理细胞。