Critical regulation of follicular helper T cell differentiation and function by Gα 13 signaling

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2021-10, Vol.118 (43)
Main Authors: Kuen, Da-Sol, Park, Miso, Ryu, Heeju, Choi, Garam, Moon, Young-Hye, Kim, Jae-Ouk, Kang, Keon Wook, Kim, Sang Geon, Chung, Yeonseok
Format: Article
Language:English
Subjects:
Animals
Cell Differentiation
GTP-Binding Protein alpha Subunits, G12-G13 - genetics
GTP-Binding Protein alpha Subunits, G12-G13 - metabolism
Lymphoid Tissue - metabolism
Mice
Mice, Inbred C57BL
Proto-Oncogene Proteins c-bcl-6 - metabolism
Receptors, CXCR5 - metabolism
rho-Associated Kinases - metabolism
rhoA GTP-Binding Protein - metabolism
Signal Transduction
T Follicular Helper Cells - cytology
Thymus Gland - cytology
Thymus Gland - growth & development
Thymus Gland - metabolism
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Summary: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 signaling in T cells plays a crucial role in inducing follicular helper T (Tfh) cell differentiation in vivo. T cell-specific Gα -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 -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 -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 -deficient mice. Conversely, ROCK inhibitor treatment hampers Tfh cell differentiation in wild-type mice. These findings unveil a crucial regulatory role of Gα -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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2108376118