Uncoupling protein 2 regulates metabolic reprogramming and fate of antigen-stimulated CD8+ T cells.
Uncoupling protein 2 regulates metabolic reprogramming and fate of antigen-stimulated CD8+ T cells.
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DOI：
10.1007/s00262-016-1851-4
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发表时间：
2016-07
期刊：
影响因子：
--
通讯作者：
Shrikant PA
中科院分区：
文献类型：
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作者：
Chaudhuri L;Srivastava RK;Kos F;Shrikant PA
Adoptive cell therapy (ACT) employing ex vivo generated tumor-antigen specific CD8+ T cells shows tumor efficacy when the transferred cells possess both effector and memory functions. New strategies based on understanding of mechanisms that balance CD8+ T cell differentiation towards effector and memory responses are highly desirable. Emerging information confirms a central role for antigen-induced metabolic reprogramming in CD8+ T cell differentiation and clonal expansion. The mitochondrial protein uncoupling protein 2 (UCP2) is induced by antigen stimulation of CD8+ T cells; however its role in metabolic reprogramming underlying differentiation and clonal expansion has not been reported. Employing genetic (siRNA) and pharmacologic (Genipin) approaches, we note that antigen-induced UCP2 expression reduces glycolysis, fatty acid synthesis (FAS) and production of reactive oxygen species (ROS) to balance differentiation with survival of effector CD8+ T cells. Inhibition of UCP2 promotes CD8+ T cell terminal differentiation into short-lived effector cells (CD62LloKLRG1HiIFNγHi) that undergo clonal contraction. These findings are the first to reveal a role for antigen-induced UCP2 expression in balancing CD8+ T cell differentiation and survival. Targeting UCP2 to regulate metabolic reprogramming of CD8+ T cells is an attractive new approach to augment efficacy of tumor therapy by ACT.
