Shan Qiang, Zeng Zhouhao, Xing Shaojun, Li Fengyin, Hartwig Stacey M, Gullicksrud Jodi A, Kurup Samarchith P, Van Braeckel-Budimir Natalija, Su Yao, Martin Matthew D, Varga Steven M, Taniuchi Ichiro, Harty John T, Peng Weiqun, Badovinac Vladimir P, Xue Hai-Hui
Department of Microbiology, University of Iowa, Iowa City, Iowa, USA.
Department of Physics, The George Washington University, Washington DC, USA.
Nat Immunol. 2017 Aug;18(8):931-939. doi: 10.1038/ni.3773. Epub 2017 Jun 12.
Activated CD8 T cells differentiate into cytotoxic effector (T) cells that eliminate target cells. How T cell identity is established and maintained is not fully understood. We found that Runx3 deficiency limited clonal expansion and impaired upregulation of cytotoxic molecules in T cells. Runx3-deficient CD8 T cells aberrantly upregulated genes characteristic of follicular helper T (T) cell lineage, including Bcl6, Tcf7 and Cxcr5. Mechanistically, the Runx3-CBFβ transcription factor complex deployed H3K27me3 to Bcl6 and Tcf7 genes to suppress the T program. Ablating Tcf7 in Runx3-deficient CD8 T cells prevented the upregulation of T genes and ameliorated their defective induction of cytotoxic genes. As such, Runx3-mediated Tcf7 repression coordinately enforced acquisition of cytotoxic functions and protected the cytotoxic lineage integrity by preventing T-lineage deviation.
活化的CD8 T细胞分化为细胞毒性效应T细胞，后者可清除靶细胞。T细胞身份如何建立和维持尚未完全明确。我们发现，Runx3缺陷限制了T细胞的克隆扩增，并损害了细胞毒性分子的上调。Runx3缺陷的CD8 T细胞异常上调了滤泡辅助性T细胞谱系特征性基因，包括Bcl6、Tcf7和Cxcr5。从机制上讲，Runx3-CBFβ转录因子复合物将H3K27me3部署到Bcl6和Tcf7基因上以抑制T细胞程序。在Runx3缺陷的CD8 T细胞中敲除Tcf7可防止T细胞基因的上调，并改善其细胞毒性基因诱导缺陷。因此，Runx3介导的Tcf7抑制通过防止T细胞谱系偏差，协同促进细胞毒性功能的获得并保护细胞毒性谱系的完整性。
