Abstract：
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.
摘要：
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），其在TGFβ存在下从抗原刺激的CD4+初始T细胞分化。tTregs相当稳定,和更多的免疫抑制，虽然iTreg细胞不太稳定，并容易分化成炎性T细胞。因此,鉴定可以促进iTreg细胞分化的小分子是自身免疫性疾病的一个有吸引力的策略。AKT/mTOR通路的抑制促进其分化。尚未确定Lck/Fyn激酶活性的抑制(AKT/mTOR途径的上游)是否可用于促进iTreg细胞的分化。这里,我们发现Srci1是Lck/Fyn的小分子抑制剂，促进FOXP3+iTreg细胞的分化。Srci1处理导致AKT/mTOR通路关键成分磷酸化抑制,包括mTOR,P70S6K,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。Srcil处理的iTreg细胞显示与tTreg细胞更相似的基因表达谱。因此，我们的研究结果表明，抑制Lck/Fyn激酶活性可以促进iTreg细胞的分化，并可能与自身免疫性疾病有关。
