Department of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
Department of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
Int Immunopharmacol. 2024 Jun 15;134:112237. doi: 10.1016/j.intimp.2024.112237. Epub 2024 May 13.
Regulatory T (Treg) cells are indispensable in maintaining the immune homeostasis and preventing autoimmune diseases. Regulatory T (Treg) cells include thymus derived Treg cells (tTregs) and peripherally induced Treg cells (iTreg), which are differentiated from antigen stimulated CD4 naïve T cells in presence of TGFβ. tTregs are quite stable, and more immune suppressive, while iTreg cells are less stable, and are prone to differentiate into inflammatory T cells. Therefore, identification of small molecules that could promote the differentiation of iTreg cells is an attractive strategy for autoimmune diseases. Inhibition of AKT/mTOR pathway promotes their differentiation. Whether inhibition of Lck/Fyn kinase activity (upstream of AKT/mTOR pathway) can be used to promote the differentiation of iTreg cells has not been determined. Here, we showed that Srci1, a small molecular inhibitor of Lck/Fyn, promoted the differentiation of FOXP3 iTreg cells. Srci1 treatment resulted in inhibition of phosphorylation of key components of AKT/mTOR pathway, including mTOR, p70 S6K, 4EBP1, and promoted the expression of Foxp3 and its target genes, thereby promoted differentiation of in vitro iTreg cells. Srci1 treated iTreg cells showed more similar gene expression profile to that of tTreg cells. Our results thus suggest that inhibition of Lck/Fyn kinase activity can promote the differentiation of iTreg cells, and may have implication in autoimmune diseases.
调节性 T（Treg）细胞在维持免疫稳态和预防自身免疫性疾病中不可或缺。调节性 T（Treg）细胞包括胸腺来源的 Treg 细胞（tTreg）和外周诱导的 Treg 细胞（iTreg），它们在外源 TGFβ的存在下，由抗原刺激的 CD4 初始 T 细胞分化而来。tTreg 细胞较为稳定，具有更强的免疫抑制作用，而 iTreg 细胞稳定性较差，易分化为炎症性 T 细胞。因此，鉴定能够促进 iTreg 细胞分化的小分子化合物是治疗自身免疫性疾病的一种有吸引力的策略。抑制 AKT/mTOR 通路可促进其分化。抑制 Lck/Fyn 激酶活性（AKT/mTOR 通路的上游）是否可用于促进 iTreg 细胞的分化尚未确定。在此，我们发现 Lck/Fyn 的小分子抑制剂 Srci1 可促进 FOXP3+iTreg 细胞的分化。Srci1 处理可抑制 AKT/mTOR 通路的关键成分磷酸化，包括 mTOR、p70 S6K、4EBP1，并促进 Foxp3 及其靶基因的表达，从而促进体外 iTreg 细胞的分化。Srci1 处理的 iTreg 细胞与 tTreg 细胞具有更相似的基因表达谱。因此，我们的研究结果表明抑制 Lck/Fyn 激酶活性可促进 iTreg 细胞的分化，可能对自身免疫性疾病具有重要意义。
