ITK signalling via the Ras/IRF4 pathway regulates the development and function of Tr1 cells

Weishan Huang,Sabrina Solouki,Avery August,Nicholas Koylass,Song-Guo Zheng

doi:10.1038/ncomms15871

Abstract

Type 1 regulatory T (Tr1) cells differentiate in response to signals engaging the T cell receptor (TCR), express high levels of the immunosuppressive cytokine IL-10, but not Foxp3, and can suppress inflammation and promote immune tolerance. Here we show that ITK, an important modulator of TCR signalling, is required for the TCR-induced development of Tr1 cells in various organs, and in the mucosal system during parasitic and viral infections. ITK kinase activity is required for mouse and human Tr1 cell differentiation. Tr1 cell development and suppressive function of Itk deficient cells can be restored by the expression of the transcription factor interferon regulatory factor 4 (IRF4). Downstream of ITK, Ras activity is responsible for Tr1 cell induction, as expression of constitutively active HRas rescues IRF4 expression and Tr1 cell differentiation in Itk−/− cells. We conclude that TCR/ITK signalling through the Ras/IRF4 pathway is required for functional development of Tr1 cells.

Highlights

Type 1 regulatory T (Tr1) cells differentiate in response to signals engaging the T cell receptor (TCR), express high levels of the immunosuppressive cytokine IL-10, but not Foxp[3], and can suppress inflammation and promote immune tolerance
We observed a significant defect in IL-10 þ Foxp[3] À LAG3 þ CD49b þ Tr1 cell differentiation systemically in blood, spleen, lung, small intestine and fat, in mice lacking the expression of inducible T cell kinase (ITK) (Fig. 1), suggesting that ITK is required for Tr1 cell development in vivo
To determine whether ITK is required for Tr1 cell development during these infections, we challenged mice with N. brasiliensis larvae or influenza A (WSN) virus, and found that ITK is required for Tr1 cell differentiation during parasitic (Fig. 2a,b) and viral (Fig. 2c,d) infections

Summary

Introduction

Type 1 regulatory T (Tr1) cells differentiate in response to signals engaging the T cell receptor (TCR), express high levels of the immunosuppressive cytokine IL-10, but not Foxp[3], and can suppress inflammation and promote immune tolerance. Beyond the finding that the cytokine IL-27 and the transcription factors interferon regulatory factor 4 (IRF4), avian musculoaponeurotic fibrosarcoma (cMAF) and aryl hydrocarbon receptor (AHR) are important for Tr1 cell differentiation, we have limited knowledge of the signalling pathways that regulate the development and, importantly, function of Tr1 cells. Our findings identify ITK as a crucial component that bridges extracellular signals, RAS signalling and IRF4 expression during Tr1 cell fate programming, and suggest that ITK signalling components are potential targets for modulating Tr1 cell development and function for clinical benefit

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