Diverse Targets of the Transcription Factor STAT3 Contribute to T Cell Pathogenicity and Homeostasis [Affymetrix Expression]. Mus musculus

STAT3, an essential transcription factor with pleiotropic functions, plays critical roles in the pathogenesis of autoimmunity. Despite recent data linking STAT3 with inflammatory bowel disease, exactly how it contributes to chronic intestinal inflammation is not known. Using a T cell transfer model of colitis we found that STAT3 expression in T cells was essential for the induction of both colitis and systemic inflammation. STAT3 was critical in modulating the balance of T helper 17 (Th17) and regulatory T (Treg) cells, as well as in promoting CD4+ T cell proliferation. We used chromatin immunoprecipitation and massive parallel sequencing (ChIP-Seq) to define the genome-wide targets of STAT3 in CD4+ T cells. We found that STAT3 bound to multiple genes involved in Th17 cell differentiation, cell activation, proliferation and survival, regulating both expression and epigenetic modifications. Thus, STAT3 orchestrates multiple critical aspects of T cell function in inflammation and homeostasis. Overall design: WT and STAT3-deficient CD4+ T cells were activated with anti-CD3 and anti-CD28, in the presence of cytokines (interleukin (IL)-6 and TGFb) or medium alone for three days. RNA was extracted and hybridized to Affymetrix microarray chips.

STAT3是一类具备多效性功能的核心转录因子，在自身免疫疾病的发病进程中发挥关键作用。尽管近期已有研究将STAT3与炎症性肠病相关联，但其具体如何参与慢性肠道炎症的发生发展仍未明确。本研究采用结肠炎的T细胞过继转移模型，发现T细胞内的STAT3表达对于结肠炎与系统性炎症的诱导均不可或缺。STAT3在调节辅助性T细胞17（T helper 17, Th17）与调节性T细胞（regulatory T, Treg）的细胞平衡，以及促进CD4+ T细胞增殖的过程中均发挥关键作用。我们通过染色质免疫共沉淀联合大规模平行测序（chromatin immunoprecipitation and massive parallel sequencing, ChIP-Seq）技术，鉴定了CD4+ T细胞内STAT3的全基因组靶标。研究发现，STAT3可结合诸多参与Th17细胞分化、细胞活化、增殖与存活的基因，并对其基因表达及表观遗传修饰进行调控。综上，STAT3可统筹调控炎症与内稳态环境下T细胞功能的多个关键方面。实验设计概况：将野生型（wild type, WT）与STAT3缺陷型CD4+ T细胞分别在细胞因子（白细胞介素（IL）-6与转化生长因子β（TGF-β））或单纯培养基存在的条件下，经抗CD3与抗CD28抗体活化培养3天。随后提取总RNA，并与Affymetrix基因芯片进行杂交实验。