Mutation of Tec family kinases alters T helper cell differentiation

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Abstract
The Tec kinases Rlk and Itk are critical for full T cell receptor (TCR)-induced activation of phospholipase C-γ and mitogen-activated protein kinase. We show here that the mutation of Rlk and Itk impaired activation of the transcription factors NFAT and AP-1 and production of both T helper type 1 (TH1) and TH2 cytokines. Consistent with these biochemical defects, Itk−/− mice did not generate effective TH2 responses when challenged with Schistosoma mansoni eggs. Paradoxically, the more severely impaired Rlk−/−Itk−/− mice were able to mount a TH2 response and produced TH2 cytokines in response to this challenge. In addition, Rlk−/−Itk−/− cells showed impaired TCR-induced repression of the TH2-inducing transcription factor GATA-3, suggesting a potential mechanism for TH2 development in these hyporesponsive cells. Thus, mutations that affect Tec kinases lead to complex alterations in CD4+ TH cell differentiation.