Division of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, Wales, UK.
Systems Immunity University Research Institute, Cardiff University, Cardiff, UK.
Nat Immunol. 2019 Apr;20(4):458-470. doi: 10.1038/s41590-019-0350-0. Epub 2019 Mar 19.
The cytokine IL-6 controls the survival, proliferation and effector characteristics of lymphocytes through activation of the transcription factors STAT1 and STAT3. While STAT3 activity is an ever-present feature of IL-6 signaling in CD4 T cells, prior activation via the T cell antigen receptor limits IL-6's control of STAT1 in effector and memory populations. Here we found that phosphorylation of STAT1 in response to IL-6 was regulated by the tyrosine phosphatases PTPN2 and PTPN22 expressed in response to the activation of naïve CD4 T cells. Transcriptomics and chromatin immunoprecipitation-sequencing (ChIP-seq) of IL-6 responses in naïve and effector memory CD4 T cells showed how the suppression of STAT1 activation shaped the functional identity and effector characteristics of memory CD4 T cells. Thus, tyrosine phosphatases induced by the activation of naïve T cells determine the way activated or memory CD4 T cells sense and interpret cytokine signals.
细胞因子 IL-6 通过激活转录因子 STAT1 和 STAT3 来控制淋巴细胞的存活、增殖和效应器特征。虽然 STAT3 活性是 CD4 T 细胞中 IL-6 信号传导的一个永久特征，但通过 T 细胞抗原受体的预先激活限制了 IL-6 对效应器和记忆群体中 STAT1 的控制。在这里，我们发现响应于 IL-6 的 STAT1 磷酸化受到在幼稚 CD4 T 细胞激活时表达的酪氨酸磷酸酶 PTPN2 和 PTPN22 的调节。幼稚和效应记忆 CD4 T 细胞中对 IL-6 反应的转录组学和染色质免疫沉淀测序 (ChIP-seq) 显示了 STAT1 激活的抑制如何塑造记忆 CD4 T 细胞的功能特征和效应特征。因此，幼稚 T 细胞激活诱导的酪氨酸磷酸酶决定了激活或记忆 CD4 T 细胞感知和解释细胞因子信号的方式。
