Mutation of Tec family kinases alters T helper cell differentiation

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-I and production of both T helper type I (T_HI) and T_H2 cytokines. Consistent with these biochemical defects, Itk^-/- mice did not generate effective T_H2 responses when challenged with Schistosoma mansoni eggs. Paradoxically, the more severely impaired Rlk^-/-Itk^-/- mice were able to mount a T_H2 response and produced T_H2 cytokines in response to this challenge. In addition, Rlk^-/-Itk^-/- cells showed impaired TCR-induced repression of the T_H2-inducing transcription factor GATA-3, suggesting a potential mechanism for T_H2 development in these hyporesponsive cells. Thus, mutations that affect Tec kinases lead to complex alterations in CD4⁺T_H cell differentiation.