Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation
Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation
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DOI：
10.1172/jci76012
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发表时间：
2015-01-01
影响因子：
15.9
通讯作者：
Rathmell, Jeffrey C.
中科院分区：
文献类型：
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作者：
Gerriets, Valerie A.;Kishton, Rigel J.;Rathmell, Jeffrey C.
活化的CD4(+)T细胞导致快速增殖和分化为效应性和调节性亚群。CD4(+)效应T细胞(T细胞)(Th1和Th17)和Treg亚群在代谢上是不同的，但改变T细胞群体的特定代谢差异尚不确定。在这里，我们在小鼠模型中评估了CD4(+)T细胞群，并确定炎性T细胞维持糖酵解基因的高表达并依赖高糖酵解率，而Tregs是氧化的，需要线粒体电子传输来增殖、分化和存活。代谢谱显示，丙酮酸脱氢酶(PDH)是T细胞糖酵解和氧化代谢的关键分叉点。PDH功能被PDH激酶(PDHKs)抑制。PDHK1在Th17细胞中表达，但在Th1细胞中不表达，在Tregs中低水平表达，抑制或敲除PDHK1选择性地抑制Th17细胞和增加Tregs。由于N-乙酰半胱氨酸(NAC)治疗恢复了Th17细胞的生成，这一变化在一定程度上是通过ROS介导的。此外，抑制PDHK1调节免疫，保护动物免受实验性自身免疫性脑脊髓炎的影响，减少Th17细胞，增加Tregs。总之，这些数据表明，CD4(+)亚群利用并需要不同的代谢程序，这些程序可以有针对性地控制自身免疫性和炎症性疾病中的特定T细胞群。
Activation of CD4(+) T cells results in rapid proliferation and differentiation into effector and regulatory subsets. CD4(+) effector T cell (Teff) (Th1 and Th17) and Treg subsets are metabolically distinct, yet the specific metabolic differences that modify T cell populations are uncertain. Here, we evaluated CD4(+) T cell populations in murine models and determined thatinflammatory Teffs maintain high expression of glycolytic genes and rely on high glycolytic rates, while Tregs are oxidative and require mitochondrial electron transport to proliferate, differentiate, and survive. Metabolic profiling revealed that pyruvate dehydrogenase (PDH) is a key bifurcation point between T cell glycolytic and oxidative metabolism. PDH function is inhibited by PDH kinases (PDHKs). PDHK1 was expressed in Th17 cells, but not Th1 cells, and at low levels in Tregs, and inhibition or knockdown of PDHK1 selectively suppressed Th17 cells and increased Tregs. This alteration in the CD4+ T cell populations was mediated in part through ROS, as N-acetyl cysteine (NAC) treatment restored Th17 cell generation. Moreover, inhibition of PDHK1 modulated immunity and protected animals against experimental autoimmune encephalomyelitis, decreasing Th17 cells and increasing Tregs. Together, these data show that CD4(+) subsets utilize and require distinct metabolic programs that can be targeted to control specific T cell populations in autoimmune and inflammatory diseases.