Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
Proc Natl Acad Sci U S A. 2017 Dec 12;114(50):13236-13241. doi: 10.1073/pnas.1711160114. Epub 2017 Nov 27.
CD8 T cells are preprogrammed for cytotoxic differentiation in the thymus as they acquire expression of the transcription factor Runx3. However, a subset of effector CD8 T cells (Tc17) produce IL-17 and fail to express cytotoxic genes. Here, we show that the transcription factors directing IL-17 production, STAT3 and RORγt, inhibit cytotoxicity despite persistent Runx3 expression. Cytotoxic gene repression did not require the transcription factor Thpok, which in CD4 T cells restrains Runx3 functions and cytotoxicity; and STAT3 restrained cytotoxic gene expression in CD8 T cells responding to viral infection in vivo. STAT3-induced RORγt represses cytotoxic genes by inhibiting the functions but not the expression of the "cytotoxic" transcription factors T-bet and Eomesodermin. Thus, the transcriptional circuitry directing IL-17 expression inhibits cytotoxic functions. However, by allowing expression of activators of the cytotoxic program, this inhibitory mechanism contributes to the instability of IL-17-producing T cells.
CD8 T 细胞在胸腺中获得转录因子 Runx3 的表达后，就预先编程为细胞毒性分化。然而，一部分效应 CD8 T 细胞（Tc17）产生白细胞介素-17（IL-17），而不能表达细胞毒性基因。在这里，我们表明指导 IL-17 产生的转录因子 STAT3 和 RORγt 抑制了细胞毒性，尽管持续表达了 Runx3。细胞毒性基因抑制不需要转录因子 Thpok，Thpok 在 CD4 T 细胞中抑制 Runx3 的功能和细胞毒性；STAT3 在体内病毒感染的 CD8 T 细胞中抑制细胞毒性基因的表达。STAT3 诱导的 RORγt 通过抑制“细胞毒性”转录因子 T-bet 和 Eomesodermin 的功能而不是表达来抑制细胞毒性基因。因此，指导 IL-17 表达的转录电路抑制了细胞毒性功能。然而，通过允许细胞毒性程序的激活剂表达，这种抑制机制有助于不稳定产生 IL-17 的 T 细胞。
