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 1

Syk plays a dominant role in γδTCR signaling and γδT cell development.

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Syk plays a dominant role in γδTCR signaling and γδT cell development. (...
(A and B) Flow cytometric analysis of CD3ε and TCRδ expression in thymocytes from the indicated mice 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). The total number of thymocytes is indicated above each flow cytometric plot (A). Graphs indicate the total number of γδT cells per mouse (B). (C and D) TCR-induced ERK phosphorylation in thymic γδT cells from the indicated mice on day 0 (Zap70–/–, n = 3; Sykb–/–, n = 4; and Zap70–/– Sykb–/–, n = 3). Histograms indicate p-ERK levels after a 2-minute stimulation (C). MFI relative to the nonstimulated control (D). (E) Histograms show CD5 expression in thymic γδT cells from the indicated mice at E15.5 (WT, n = 13; Zap70–/–, n = 10; Sykb–/–, n = 9; and Zap70–/– Sykb–/–, n = 2) and on day 0 (WT, n = 17; Zap70–/–, n = 3; Sykb–/–, n = 7; and Zap70–/– Sykb–/–, n = 5). Graphs indicate the MFI relative to WT mice. All data represent the mean ± SEM. *P < 0.05 and **P < 0.01, by 1-way ANOVA (B and E) and 2-way ANOVA (D). Data represent the combined results of 3 independent experiments (A, B, and E) or a single experiment (C and D). Max, maximum.