Active STAT5 Regulates T-bet and Eomesodermin Expression in CD8 T Cells and Imprints a T-bet-Dependent Tc1 Program with Repressed IL-6/TGF-β1 Signaling
Active STAT5 Regulates T-bet and Eomesodermin Expression in CD8 T Cells and Imprints a T-bet-Dependent Tc1 Program with Repressed IL-6/TGF-β1 Signaling
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DOI：
10.4049/jimmunol.1300319
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发表时间：
2013-10-01
影响因子：
4.4
通讯作者：
Auphan-Anezin, Nathalie
中科院分区：
文献类型：
--
作者：
Grange, Magali;Verdeil, Gregory;Auphan-Anezin, Nathalie
在过继治疗中，发现表达活性STAT 5（STAT 5CA）转录因子的CD 8 T细胞在长期持久性、浸润原位小鼠黑色素瘤的能力、在其微环境中茁壮成长并诱导其消退方面上级未操作的对应物。然而，维持这些特性的分子机制尚未确定。在这项研究中，我们报告了STAT 5 CA诱导控制组织归巢、溶细胞颗粒组成、1型CD 8细胞毒性T细胞相关效应分子颗粒酶B+、IFN-γ（+）、TNF-alpha（+）和CCL 3（+）的基因的持续表达，但不诱导IL-2以及转录因子T-bet和eomesodermin（Eomes）。染色质免疫沉淀测序分析鉴定了具有STAT 5在体内长期维持的表达STAT 5CA的CD 8 T细胞中结合的调控区的基因。该分析鉴定了34%的在表达和不表达STAT 5CA的效应T细胞之间差异表达的基因作为直接STAT 5CA靶基因，包括编码T-bet、Eomes和颗粒酶B的基因。此外，编码IL-6 R和TGF β RII亚基的基因被稳定抑制，导致响应于IL-6和TGF β 1的产生IL-17的CD 8 T细胞极化减弱。T-bet的缺乏不影响组织中STAT 5CA驱动的T细胞的积累或其颗粒酶B表达，但恢复了IL-2分泌以及IL-6 R和TGF β R II表达和信号传导，如IL-17诱导所示。因此，协同的STAT 5/T-bet/Eomes调节控制归巢、长期维持、回忆应答和对产生IL-17的CD 8 T细胞极化的抗性，同时维持有效的1型CD 8细胞毒性T细胞程序（颗粒酶B+、IFN-γ（+））的表达。
In adoptive therapy, CD8 T cells expressing active STAT5 (STAT5CA) transcription factors were found to be superior to unmanipulated counterparts in long-term persistence, capacity to infiltrate autochthonous mouse melanomas, thrive in their microenvironment, and induce their regression. However, the molecular mechanisms sustaining these properties were undefined. In this study, we report that STAT5CA induced sustained expression of genes controlling tissue homing, cytolytic granule composition, type 1 CD8 cytotoxic T cell-associated effector molecules granzyme B+, IFN-gamma(+), TNF-alpha(+), and CCL3(+), but not IL-2, and transcription factors T-bet and eomesodermin (Eomes). Chromatin immunoprecipitation sequencing analyses identified the genes possessing regulatory regions to which STAT5 bound in long-term in vivo maintained STAT5CA-expressing CD8 T cells. This analysis identified 34% of the genes differentially expressed between STAT5CA-expressing and nonexpressing effector T cells as direct STAT5CA target genes, including those encoding T-bet, Eomes, and granzyme B. Additionally, genes encoding the IL-6R and TGFbRII subunits were stably repressed, resulting in dampened IL-17-producing CD8 T cell polarization in response to IL-6 and TGF-beta 1. The absence of T-bet did not affect STAT5CA-driven accumulation of the T cells in tissue or their granzyme B expression but restored IL-2 secretion and IL-6R and TGFbRII expression and signaling, as illustrated by IL-17 induction. Therefore, concerted STAT5/T-bet/Eomes regulation controls homing, long-term maintenance, recall responses, and resistance to polarization towards IL-17-producing CD8 T cells while maintaining expression of an efficient type 1 CD8 cytotoxic T cell program (granzyme B+, IFN-gamma(+)).