Institute of Immunology and School of Medicine, Tsinghua University, Beijing, China.
Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
Immunity. 2021 Dec 14;54(12):2740-2755.e6. doi: 10.1016/j.immuni.2021.09.018. Epub 2021 Oct 12.
T follicular helper (Tfh) cells play essential roles in regulating humoral immunity, especially germinal center reactions. However, how CD4 T cells integrate the antigenic and costimulatory signals in Tfh cell development is still poorly understood. Here, we found that phorbol 12-myristate 13-acetate (PMA) + ionomycin (P+I) stimulation, together with interleukin-6 (IL-6), potently induce Tfh cell-like transcriptomic programs in vitro. The ERK kinase pathway was attenuated under P+I stimulation; ERK2 inhibition enhanced Tfh cell development in vitro and in vivo. We observed that inducible T cell costimulator (ICOS), but not CD28, lacked the ability to activate ERK, which was important in sustaining Tfh cell development. The transcription factor Zfp831, whose expression was repressed by ERK, promoted Tfh cell differentiation by directly upregulating the expression of the transcription factors Bcl6 and Tcf7. We have hence identified an ERK-Zfp831 axis, regulated by costimulation signaling, in critical regulation of Tfh cell development.
滤泡辅助 T（Tfh）细胞在调节体液免疫方面发挥着重要作用，特别是在生发中心反应中。然而，CD4 T 细胞如何整合抗原和共刺激信号以促进 Tfh 细胞的发育仍知之甚少。在这里，我们发现佛波醇 12-肉豆蔻酸 13-乙酸酯（PMA）+离子霉素（P+I）刺激，与白细胞介素 6（IL-6）一起，在体外强烈诱导 Tfh 样转录组程序。ERK 激酶途径在 P+I 刺激下被减弱；ERK2 抑制增强了体外和体内的 Tfh 细胞发育。我们观察到，可诱导的 T 细胞共刺激物（ICOS），而不是 CD28，缺乏激活 ERK 的能力，而 ERK 对于维持 Tfh 细胞的发育是重要的。转录因子 Zfp831 的表达受到 ERK 的抑制，通过直接上调转录因子 Bcl6 和 Tcf7 的表达来促进 Tfh 细胞分化。因此，我们已经确定了一个由共刺激信号调节的 ERK-Zfp831 轴，在 Tfh 细胞发育的关键调控中发挥作用。
