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 6

Syk mediates the Lat-independent TCR signal to the PI3K/Akt pathway.

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Syk mediates the Lat-independent TCR signal to the PI3K/Akt pathway. (A)...
(A) Flow cytometric profiles for CD3ε and TCRδ in total thymocytes from 5-week-old WT and Lat–/– mice. The total number of thymocytes is shown above each flow cytometric plot (n = 3). (B) Flow cytometric analysis of CD5 expression in thymic γδT cells (n = 3). (C) TCR-induced ERK phosphorylation in thymic γδT cells. Graph indicates the MFI relative to the nonstimulated control (n = 3). (D) TCR-induced Akt phosphorylation in thymic γδT cells pretreated or not with IC87114 (10 μM). Graph shows the MFI relative to the nonstimulated control (n = 3). (E) Flow cytometric analysis of Zap70 and Syk expression in thymic γδT cells from 5-week-old WT and Lat–/– mice (n = 3). (F) TCR-induced Akt phosphorylation in Lat–/– γδT cells pretreated or not with BAY61-3606 (10 μM). Graph shows the MFI relative to the nonstimulated control (n = 3). (G) Intracellular staining for IL-17A production in neonatal thymic γδT cells from WT mice (n = 3) and Lat–/– mice (n = 5) after stimulation with PMA and ionomycin. The number of IL-17A+ γδT cells (per mouse) is shown. All data represent the mean ± SEM. *P < 0.05 and **P < 0.01, by 2-way ANOVA (C, D, and F) and unpaired t test (G). Data represent 2 independent experiments (A, B, D, F, and G) or a single experiment (C and E).