ITK signaling via the Ras/IRF4 pathway regulates the development and function of type 1 regulatory T cells

Abstract

Abstract Type 1 regulatory T (Tr1) cells differentiate in response to signals engaging 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, using IL-10GFP/Foxp3RFP dual reporter transgenic mouse system, we show that ITK, a key modulator of TCR signaling, is required for the development of Tr1 cells in various organs following TCR activation, and in the mucosal system during parasitic and viral infections. ITK kinase activity is required for mouse and human Tr1 cell fate programming and regulates the balance between IL-10 and IFN-γ production during Tr1 cell differentiation. The requirement for ITK function during Tr1 cell development and suppressive function can be restored by the expression of the transcription factor IRF4. Downstream of ITK, Ras, and MAP kinases ERK1/2, p38 and JNK, are required for Tr1 cell differentiation, but not Th17 cell differentiation. We have previously shown that Th17 differentiation is also dependent on ITK signaling. However, in the absence of ITK, expression of the constitutively active HRasG12V rescued IRF4 expression and Tr1 cell differentiation, but failed to restore Th17 cell differentiation. We conclude that the TCR/ITK signaling through the Ras/MAPK/IRF4 pathway is specifically required for functional development of Tr1 cells, and that targeting these signaling components may be of therapeutic benefit.