γδTCR recruits the Syk/PI3K axis to drive proinflammatory differentiation program
Ryunosuke Muro, … , Hiroshi Takayanagi, Harumi Suzuki
Ryunosuke Muro, … , Hiroshi Takayanagi, Harumi Suzuki
Published December 4, 2017
Citation Information: J Clin Invest. 2018;128(1):415-426. https://doi.org/10.1172/JCI95837.
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Research Article Cell biology Immunology

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

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.

Authors

Ryunosuke Muro, Takeshi Nitta, Kenta Nakano, Tadashi Okamura, Hiroshi Takayanagi, Harumi Suzuki

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Figure 2

Syk is required for γδT17 development.

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Syk is required for γδT17 development. (A) Intracellular staining for IL...
(A) Intracellular staining for IL-17A production after stimulation with PMA and ionomycin in total or Vγ4+ γδT thymic cells from the indicated mice on day 0. SSC-A, side scatter area.(B) Total IL-17–producing and Vγ4+ γδT thymic cell numbers per mouse on day 0 (WT, n = 23; Zap70–/–, n = 4; Sykb–/–, n = 7; and Zap70–/– Sykb–/–, n = 5). (C) Representative profiles for cell-surface TCRδ and intracellular RORγt expression in thymic γδT cells (n = 4–5). Graphs indicate the frequency of RORγt cells in total and Vγ4+ γδT cells. (D) Number of Vγ4, Vγ1, Vγ5, and Vγ6 (17D1+Vγ5–) cells per mouse at E15.5 (WT, n = 16; Zap70–/–, n = 10; Sykb–/–, n = 8; and Zap70–/– Sykb–/–, n = 2) and on day 0 (WT, n = 19; Zap70–/–, n = 4; Sykb–/–, n = 7; and Zap70–/– Sykb–/–, n = 8). (E) Total IL-17–producing and Vγ4+ γδT cell numbers from the thymus, spleen, and lungs of the indicated fetal liver chimeric mice. The mice were analyzed 8 weeks after the reconstitution. Data represent the mean ± SEM. *P < 0.05 and **P < 0.01, by 1-way ANOVA (B–D) and unpaired t test (E). Data represent the combined results of 3 independent experiments (A–D) or 2 independent experiments (E).