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J Clin Invest. 2018 Jan 2;128(1):415-426. doi: 10.1172/JCI95837. Epub 2017 Dec 4.

γδTCR recruits the Syk/PI3K axis to drive proinflammatory differentiation program.

Author information

1
Department of Immunology and Pathology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan.
2
Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
3
Department of Laboratory Animal Medicine, and.
4
Section of Animal Models, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.

Abstract

γδT cells produce inflammatory cytokines and have been implicated in the pathogenesis of cancer, infectious diseases, and autoimmunity. The T cell receptor (TCR) signal transduction that specifically regulates the development of IL-17-producing γδT (γδT17) cells largely remains unclear. Here, we showed that the receptor proximal tyrosine kinase Syk is essential for γδTCR signal transduction and development of γδT17 in the mouse thymus. Zap70, another tyrosine kinase essential for the development of αβT cells, failed to functionally substitute for Syk in the development of γδT17. Syk induced the activation of the PI3K/Akt pathway upon γδTCR stimulation. Mice deficient in PI3K signaling exhibited a complete loss of γδT17, without impaired development of IFN-γ-producing γδT cells. Moreover, γδT17-dependent skin inflammation was ameliorated in mice deficient in RhoH, an adaptor known to recruit Syk. Thus, we deciphered lineage-specific TCR signaling and identified the Syk/PI3K pathway as a critical determinant of proinflammatory γδT cell differentiation.

KEYWORDS:

Cell Biology; Cytokines; Immunology; Signal transduction; T cell development

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