ACLY and ACSS2 link nutrient-dependent chromatin accessibility to regulation of CD8 T cell effector responses

Coordination of cellular metabolism is essential for optimal T cell responses. Here, we identify cytosolic acetyl-CoA production as an essential metabolic node for CD8 T cell function in vivo. We show that CD8 T cell responses to infection depend on acetyl-CoA derived from citrate via the enzyme Acly (ATP citrate lyase). However, ablation of Acly triggers an alternative, acetate-dependent pathway for acetyl-CoA production mediated by Acss2 (acyl-CoA synthetase short chain family member 2). Mechanistically, acetate fuels both the TCA cycle and cytosolic acetyl-CoA production, impacting T cell effector responses, acetate-dependent histone acetylation, and chromatin accessibility at effector gene loci. When Acly is functional, Acss2 is not required, suggesting acetate is not an obligate metabolic substrate for CD8 T cell function. However, deletion of Acly renders CD8 T cells dependent on acetate (via Acss2) to maintain acetyl-CoA production and effector function. Thus, together Acly and Acss2 coordinate cytosolic acetyl-CoA production in CD8 T cells to maintain chromatin accessibility and T cell effector function. C57BL/6 mice (3 biological replicates) were infected with LCMV-Armstrong. At 8 dpi, mice were sacrificed, and single cell suspensions generated

细胞代谢的协同调控对于实现最佳T细胞应答至关重要。本研究鉴定发现，胞质乙酰辅酶A（acetyl-CoA）生成是体内CD8 T细胞功能发挥所必需的代谢节点。我们证实，CD8 T细胞针对感染的应答依赖于由ATP柠檬酸裂解酶（ATP citrate lyase，Acly）介导的、源自柠檬酸的乙酰辅酶A。然而，敲除Acly可触发一条由酰基辅酶A合成酶短链家族成员2（acyl-CoA synthetase short chain family member 2，Acss2）介导的乙酸盐依赖性乙酰辅酶A生成替代通路。机制层面来看，乙酸盐可为三羧酸循环（tricarboxylic acid cycle，TCA cycle）与胞质乙酰辅酶A生成供能，进而影响T细胞效应应答、乙酸盐依赖性组蛋白乙酰化以及效应基因位点处的染色质可及性。当Acly功能完整时，Acss2并非必需，这提示乙酸盐并非CD8 T细胞功能发挥所必需的代谢底物。然而，敲除Acly会使CD8 T细胞依赖乙酸盐（通过Acss2通路）以维持乙酰辅酶A生成与效应功能。综上，Acly与Acss2协同调控CD8 T细胞内的胞质乙酰辅酶A生成，从而维持染色质可及性与T细胞效应功能。本研究用淋巴细胞脉络丛脑膜炎病毒-阿姆斯特丹毒株（LCMV-Armstrong）感染C57BL/6小鼠（3个生物学重复），于感染后第8天（days post infection，dpi）处死小鼠并制备单细胞悬液。