先天淋巴细胞(ILC)已被鉴定为淋巴细胞的异质群体,反映了适应性T细胞的细胞因子和转录谱。关键转录因子之间的动态平衡决定了异质性,可塑性,和ILC子集的功能。转录因子ThPOK在生物进化中高度保守,在T细胞分化中发挥重要作用。然而,ThPOK在ILC3中的功能尚未确定。这里,我们发现ThPOK调节ILC3的稳态,如缺乏ThPOK的小鼠显示NKp46+ILC3s减少和CCR6-NKp46-ILC3s增加。由于NKp46+ILC3s的IFN-γ分泌受损,ThPOK缺陷型小鼠对鼠伤寒沙门氏菌感染更敏感。此外,ThPOK通过负调节IL-17A分泌参与ILC3介导的控制。ThPOK通过抑制RORγt来保留NKp46+ILC3的身份,间接释放T-bet表达式。在分子水平上,ThPOK直接与Rorc和Il23r结合以抑制它们的表达,这进一步调节IL-17A的分泌。总的来说,我们的分析揭示了ThPOK在ILC3亚群的稳态和功能中的关键作用.
Innate lymphoid cells (ILCs) have been identified as a heterogeneous population of lymphocytes that mirrors the cytokine and transcriptional profile of adaptive T cells. The dynamic balance between key transcription factors determines the heterogeneity, plasticity, and functions of ILC subsets. The transcription factor
ThPOK is highly conserved in biological evolution and exerts pivotal functions in the differentiation of T cells. However, the function of
ThPOK in ILC3s has not been identified. Here, we found that
ThPOK regulated the homeostasis of ILC3s, as mice lacking
ThPOK showed decreased NKp46+ ILC3s and increased CCR6- NKp46- ILC3s.
ThPOK-deficient mice were more sensitive to S. typhimurium infection due to the impaired IFN-γ secretion of NKp46+ ILC3s. Furthermore, ThPOK participates in ILC3-mediated control of C. rodentium infection by negatively regulating IL-17A secretion. ThPOK preserves the identity of NKp46+ ILC3s by repressing RORγt, which indirectly releases T-bet expression. On the molecular level, ThPOK directly binds to Rorc and Il23r to restrain their expression which further modulates IL-17A secretion. Collectively, our analysis revealed a critical role of
ThPOK in the homeostasis and functions of ILC3 subsets.