Mutation of Tec family kinase alters T helper cell differentiation

The Tec kinases RIk and Itk are critical for full T cell receptor (TCR)-induced activation of phospholipase C-gamma and mitogen-activated protein kinase. We show here that the mutation of RIk and Itk impaired activation of the transcription factors NFAT and AP-1 and production of both T helper type I (T(H)1) and T(H)2 cytokines. Consistent with these biochemical defects, Itk(-/-) mice did not generate effective T(H)2 responses when challenged with Schistosoma mansoni eggs. Paradoxically, the more severely impaired RIk(-/-)Itk(-/-) mice were able to mount a T(H)2 response and produced T(H)2 cytokines in response to this challenge. In addition, RIk(-/-)Itk(-/-) cells showed impaired TCR-induced repression of the T(H)2-inducing transcription factor GATA-3, suggesting a potential mechanism for T(H)2 development in these hyporesponsive cells. Thus, mutations that affect Tec kinases lead to complex alterations in CD4(+)T(H) cell differentiation.