Mirlekar B, Ghorai S, Khetmalas M, Bopanna R, Chattopadhyay S
Mucosal Immunol. 2015 Nov;8(6):1184-200. doi: 10.1038/mi.2015.42.
Regulatory T (Treg) cells are essential for self-tolerance and immune homeostasis. Transcription factor Foxp3, a positive regulator of Treg cell differentiation, has been studied to some extent. Signal transducer and activator of transcription factor 3 (STAT3) is known to negatively regulate Foxp3. It is not clear how STAT3 is regulated during Treg differentiation. We show that SMAR1, a known transcription factor and tumor suppressor, is directly involved in maintaining Treg cell fate decision. T-cell-specific conditional knockdown of SMAR1 exhibits increased susceptibility towards inflammatory disorders, such as colitis. The suppressive function of Treg cells is compromised in the absence of SMAR1 leading to increased T helper type 17 (Th17) differentiation and inflammation. Compared with wild-type, the SMAR1(-/-) Treg cells showed increased susceptibility of inflammatory bowel disease in Rag1(-/ -) mice, indicating the role of SMAR1 in compromising Treg cell differentiation resulting in severe colitis. We show that SMAR1 negatively regulate STAT3 expression favoring Foxp3 expression and Treg cell differentiation. SMAR1 binds to the MAR element of STAT3 promoter, present adjacent to interleukin-6 response elements. Thus Foxp3, a major driver of Treg cell differentiation, is regulated by SMAR1 via STAT3 and a fine-tune balance between Treg and Th17 phenotype is maintained.
调节性T（Treg）细胞对于自身耐受和免疫稳态至关重要。转录因子Foxp3作为Treg细胞分化的正向调节因子，已得到一定程度的研究。已知信号转导及转录激活因子3（STAT3）对Foxp3起负向调节作用。目前尚不清楚在Treg分化过程中STAT3是如何被调节的。我们发现，已知的转录因子和肿瘤抑制因子SMAR1直接参与维持Treg细胞命运决定。T细胞特异性条件性敲低SMAR1会增加对炎症性疾病（如结肠炎）的易感性。在缺乏SMAR1的情况下，Treg细胞的抑制功能受损，导致辅助性T细胞17（Th17）分化增加和炎症反应。与野生型相比，SMAR1（-/-）Treg细胞在Rag1（-/-）小鼠中对炎症性肠病的易感性增加，表明SMAR1在损害Treg细胞分化导致严重结肠炎中所起的作用。我们发现SMAR1负向调节STAT3表达，有利于Foxp3表达和Treg细胞分化。SMAR1与STAT3启动子的MAR元件结合，该元件位于白细胞介素-6反应元件附近。因此，作为Treg细胞分化主要驱动因子的Foxp3通过SMAR1经由STAT3进行调节，从而维持Treg和Th17表型之间的精细平衡。
