Intlekofer Andrew M, Takemoto Naofumi, Kao Charlly, Banerjee Arnob, Schambach Felix, Northrop John K, Shen Hao, Wherry E John, Reiner Steven L
Abramson Family Cancer Research Institute, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
J Exp Med. 2007 Sep 3;204(9):2015-21. doi: 10.1084/jem.20070841. Epub 2007 Aug 13.
Immunity to intracellular pathogens requires dynamic balance between terminal differentiation of short-lived, cytotoxic effector CD8+ T cells and self-renewal of central-memory CD8+ T cells. We now show that T-bet represses transcription of IL-7Ralpha and drives differentiation of effector and effector-memory CD8+ T cells at the expense of central-memory cells. We also found T-bet to be overexpressed in CD8+ T cells that differentiated in the absence of CD4+ T cell help, a condition that is associated with defective central-memory formation. Finally, deletion of T-bet corrected the abnormal phenotypic and functional properties of "unhelped" memory CD8+ T cells. T-bet, thus, appears to function as a molecular switch between central- and effector-memory cell differentiation. Antagonism of T-bet may, therefore, represent a novel strategy to offset dysfunctional programming of memory CD8+ T cells.
对细胞内病原体的免疫需要在短命的细胞毒性效应CD8 + T细胞的终末分化与中枢记忆CD8 + T细胞的自我更新之间保持动态平衡。我们现在表明，T-bet抑制IL-7Rα的转录，并以中枢记忆细胞为代价驱动效应和效应记忆CD8 + T细胞的分化。我们还发现T-bet在缺乏CD4 + T细胞辅助的情况下分化的CD8 + T细胞中过表达，这种情况与中枢记忆形成缺陷有关。最后，删除T-bet纠正了“未获得辅助”的记忆CD8 + T细胞的异常表型和功能特性。因此，T-bet似乎起着中枢记忆和效应记忆细胞分化之间分子开关的作用。因此，拮抗T-bet可能代表一种抵消记忆CD8 + T细胞功能失调编程的新策略。
