IL-2–Inducible T Cell Kinase Tunes T Regulatory Cell Development and Is Required for Suppressive Function

Abstract

ITK is a key signaling mediator downstream of TcR, mediating T cell positive selection, innate T cell and CD4+ Th2/Th17 differentiation. Here we show that ITK also negatively tunes IL-2-induced expansion of Foxp3+ regulatory T cells (Treg). In vivo, Treg abundance is inversely correlated with ITK expression, and iTreg development is inversely dependent on ITK kinase activity. While Treg development normally requires both hematopoietic and thymic MHC class 2 (MHC2) expression, the absence of ITK allows Treg development with MHC2 expression in either compartment with preference for selection by thymic MHC2, suggesting a gatekeeper role of ITK in ensuring that only Treg cells selected by both thymic and hematopoietic MHC2 survive selection. Although ITK suppresses Treg development and is not required for maintenance of NRP1+ natural Treg cells in the periphery, it is indispensable for Treg functional suppression of naïve CD4+ T cell-induced colitis in Rag−/− recipients. ITK thus regulates the development and function of Treg cells.

A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression

“…We therefore considered whether the inhibitory effect of PRN694 on colitis might be due to enhanced differentiation of Foxp3 + iTreg cells in the inhibitor-treated mice. Instead, analysis of T cells at 7-weeks post-transfer indicated that PRN694 significantly reduced the proportions of CD4 + T cells expressing Foxp3 compared to controls, a result consistent with the findings of Huang et al (14). This was evident in all organs examined (Fig.…”

“…Specifically, Itk −/− T cells showed reduced IL-17A production and increased forkhead box P3 (Foxp3) expression following in vitro polarization (12, 13). In addition, Itk −/− T cells provided enhanced regulatory T cell (Treg)-mediated protection in an adoptive transfer model of colitis, due to their increased potential to upregulate Foxp3 (13), although another study found that Itk −/− Tregs were unable to protect against T cell mediated colitis (14). In spite of some of disparities between studies, in general, these findings have provided impetus for the development of small molecule ITK kinase inhibitors, with the intent of using them as treatments for atopic diseases, as well as for their potential as an immunosuppressant to block graft rejection or autoimmunity.…”

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

“…We and others have previously shown ITK as a negative regulator of Foxp3 + Treg cell development1617, but its role in CD4 + Foxp3 − IL-10 + Tr1 cell development is unclear. To determine the role of ITK in Tr1 cell differentiation in vivo , we injected WT and Itk −/− IL-10 GFP /Foxp3 RFP dual reporter mice with an anti-CD3ε antibody that has been shown to stimulate pronounced Tr1 cell development through TCR activation in vivo 3.…”

T cell receptor signalling in the control of regulatory T cell differentiation and function

“…Accordingly, Itk deficiency results in enhanced iTreg cell differentiation 67 . The absence of Itk also results in an increased tTreg cell frequency in vivo 68 , but it remains to be determined whether Pten-mediated repression of Akt is affected. An important downstream target of Akt is the tuberous sclerosis (TSC) complex that suppresses mTOR complex 1 (mTORC1) activation by functioning as a GTPase-activating protein for the small GTPase Rheb 69 .…”