Center for Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China.
Department of Microbiology and Immunology, Cornell University, Ithaca, New York 14853, USA.
Nat Commun. 2017 Jun 21;8:15871. doi: 10.1038/ncomms15871.
Type 1 regulatory T (Tr1) cells differentiate in response to signals engaging the T cell receptor (TCR), express high levels of the immunosuppressive cytokine IL-10, but not Foxp3, and can suppress inflammation and promote immune tolerance. Here we show that ITK, an important modulator of TCR signalling, is required for the TCR-induced development of Tr1 cells in various organs, and in the mucosal system during parasitic and viral infections. ITK kinase activity is required for mouse and human Tr1 cell differentiation. Tr1 cell development and suppressive function of Itk deficient cells can be restored by the expression of the transcription factor interferon regulatory factor 4 (IRF4). Downstream of ITK, Ras activity is responsible for Tr1 cell induction, as expression of constitutively active HRas rescues IRF4 expression and Tr1 cell differentiation in Itk cells. We conclude that TCR/ITK signalling through the Ras/IRF4 pathway is required for functional development of Tr1 cells.
1 型调节性 T（Tr1）细胞在与 T 细胞受体（TCR）结合的信号刺激下分化，表达高水平的免疫抑制细胞因子 IL-10，但不表达 Foxp3，可抑制炎症并促进免疫耐受。在这里，我们发现 ITK（TCR 信号的重要调节剂）是各种器官中 TCR 诱导的 Tr1 细胞发育所必需的，也是寄生虫和病毒感染期间黏膜系统中必需的。ITK 激酶活性对于人和小鼠 Tr1 细胞分化是必需的。ITK 缺陷细胞的 Tr1 细胞发育和抑制功能可以通过转录因子干扰素调节因子 4（IRF4）的表达来恢复。在 ITK 下游，Ras 活性负责 Tr1 细胞的诱导，因为组成性激活的 HRas 可挽救 Itk 细胞中 IRF4 的表达和 Tr1 细胞分化。我们得出结论，TCR/ITK 通过 Ras/IRF4 途径的信号转导对于 Tr1 细胞的功能发育是必需的。
