γδTCR recruits the Syk/PI3K axis to drive proinflammatory differentiation program
Ryunosuke Muro, … , Hiroshi Takayanagi, Harumi Suzuki
Ryunosuke Muro, … , Hiroshi Takayanagi, Harumi Suzuki
Published January 2, 2018
Citation Information: J Clin Invest. 2018;128(1):415-426. https://doi.org/10.1172/JCI95837.
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Categories: 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 7

RhoH mediates the γδTCR signaling required for γδT17 development.

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RhoH mediates the γδTCR signaling required for γδT17 development. (A and...
(A and B) TCR-induced ERK and Akt phosphorylation in thymic γδT cells from WT (n = 3) and Rhoh–/– mice (n = 3). (C) Representative CD5 expression profiles in thymic γδT cells (n = 3). (D) Number of cells in the indicated thymic γδT subsets from WT and Rhoh–/– mice at E15.5 (WT, n = 5; Rhoh–/–, n = 5) and on day 0 (WT, n = 8; Rhoh–/–, n = 9). (E and F) Staining for Vγ4 and IL-17A in thymic (day 0; WT, n = 4; Rhoh–/–, n = 4) and splenic (6-week-old; WT, n = 8; Rhoh–/–, n = 8) γδT cells after stimulation with PMA and ionomycin. Graph shows the quantification of IL-17A+ γδT cells (per mouse). (G–I) WT and Rhoh–/– mice were treated daily for 7 days with IMQ cream or control cream on the ear (n = 3). Kinetics of IMQ-induced ear swelling (G), representative H&E staining of ear sections on day 7 (H), and flow cytometric analysis of IL-17A+ cells in γδT cells from ear-draining lymph nodes on day 7 (I). Scale bar: 100 μm. All data represent the mean ± SEM. *P < 0.05 and **P < 0.01, by 2-way ANOVA (A, B, and G)and unpaired t test (D and F). Data represent more than 2 independent experiments (A–F) or a single experiment (G–I).