期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：43
DOI：10.1073/pnas.2108376118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Optimal follicular helper T (Tfh) cell differentiation and function are required for effective humoral immunity against infection, while improper Tfh cell responses are associated with autoimmunity and allergy. We demonstrate that Gα
13—a Gα protein subunit known to be involved in mediating signals related to cytoskeletal integrity, chemotaxis, and migration—acts as an essential positive regulator in Tfh cell development and function. The deletion of Gα
13 in T cells results in dampened germinal center reactions in immunization and viral infection models. Mechanistically, Gα
13-RhoA-ROCK2 axis is responsible for the Tfh cell differentiation from naïve precursors, and Rho agonists recuperate hampered Tfh cell function in Gα
13-deficient mice. Such mechanistic insight underscores the possibility of targeting Gα
13-mediated signaling to maneuver Tfh cell responses.
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 Gα
13 signaling in T cells plays a crucial role in inducing follicular helper T (Tfh) cell differentiation in vivo. T cell–specific Gα
13-deficient mice have diminished Tfh cell responses in a cell-intrinsic manner in response to immunization, lymphocytic choriomeningitis virus infection, and allergen challenges. Moreover, Gα
13-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, Gα
13-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 Gα
13-deficient mice. Conversely, ROCK inhibitor treatment hampers Tfh cell differentiation in wild-type mice. These findings unveil a crucial regulatory role of Gα
13-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.
关键词：Gα13; Tfh cell; germinal center reaction; ROCK
