Proceedings of the National Academy of Sciences of the United States of America ( IF 11.1 ) Pub Date : 2021-10-26 , DOI: 10.1073/pnas.2108376118 Da-Sol Kuen 1, 2 , Miso Park 2, 3 , Heeju Ryu 1 , Garam Choi 1 , Young-Hye Moon 4 , Jae-Ouk Kim 4 , Keon Wook Kang 2, 3 , Sang Geon Kim 5 , Yeonseok Chung 2, 6
GPCR-Gα protein–mediated signal transduction contributes to spatiotemporal interactions between immune cells to fine-tune and facilitate the process of inflammation and host protection. Beyond this, however, how Gα proteins contribute to the helper T cell subset differentiation and adaptive response have been underappreciated. Here, we found that Gα13 signaling in T cells plays a crucial role in inducing follicular helper T (Tfh) cell differentiation in vivo. T cell–specific Gα13-deficient mice have diminished Tfh cell responses in a cell-intrinsic manner in response to immunization, lymphocytic choriomeningitis virus infection, and allergen challenges. Moreover, Gα13-deficient Tfh cells express reduced levels of Bcl-6 and CXCR5 and are functionally impaired in their ability to adhere to and stimulate B cells. Mechanistically, Gα13-deficient Tfh cells harbor defective Rho-ROCK2 activation, and Rho agonist treatment recuperates Tfh cell differentiation and expression of Bcl-6 and CXCR5 in Tfh cells of T cell–specific Gα13-deficient mice. Conversely, ROCK inhibitor treatment hampers Tfh cell differentiation in wild-type mice. These findings unveil a crucial regulatory role of Gα13-Rho-ROCK axis in optimal Tfh cell differentiation and function, which might be a promising target for pharmacologic intervention in vaccine development as well as antibody-mediated immune disorders.
中文翻译:
G{alpha}13 信号传导对滤泡辅助性 T 细胞分化和功能的关键调控 [免疫学和炎症]
GPCR-Gα 蛋白介导的信号转导有助于免疫细胞之间的时空相互作用,以微调和促进炎症和宿主保护过程。然而,除此之外,Gα 蛋白如何促进辅助 T 细胞亚群分化和适应性反应还没有得到充分认识。在这里,我们发现T 细胞中的Gα 13信号传导在体内诱导滤泡辅助性 T (Tfh) 细胞分化中起着至关重要的作用。T 细胞特异性 Gα 13缺陷小鼠以细胞内在方式减少了 Tfh 细胞反应,以响应免疫、淋巴细胞脉络丛脑膜炎病毒感染和过敏原挑战。此外,Gα 13- 缺陷的 Tfh 细胞表达的 Bcl-6 和 CXCR5 水平降低,并且它们粘附和刺激 B 细胞的能力受损。从机制上讲,Gα 13缺陷的 Tfh 细胞具有缺陷的 Rho-ROCK2 激活,并且 Rho 激动剂治疗恢复了 Tfh 细胞分化以及 T 细胞特异性 Gα 13缺陷小鼠的Tfh 细胞中 Bcl-6 和 CXCR5 的表达。相反,ROCK 抑制剂治疗会阻碍野生型小鼠的 Tfh 细胞分化。这些发现揭示了 Gα 13 -Rho-ROCK 轴在最佳 Tfh 细胞分化和功能中的关键调节作用,这可能是疫苗开发和抗体介导的免疫疾病中药物干预的有希望的目标。