The Tec family of tyrosine kinases have been implicated as important mediators of polarized cytokine production and Th2 cell differentiation. Rlk is preferentially expressed in Th1 cells and Itk is important in Th2 response. Numerous studies have implicated alterations in the strength of TCR-mediated signals as playing important roles in Th cell differentiation. Researchers at the NIH have developed transgenic mouse models in order to address these issues. Rlk-deficient mice and Rlk/Itk double-deficient mice were generated and have been shown to have defects in TCR responses including proliferation, cytokine production and apoptosis in vitro and adaptive immune response to infectious agents in vivo (Science (1999) 284, 638-641; Nature Immunol. (2001) 2: 1183-188). Molecular analyses of cells from these mice indicate that these kinases are critical for proper regulation of phospholipase C, calcium mobilisation and ERK activation as well as activation of downstream transcription factors in response to T cell receptor stimulation. Defects are minor in Rlk-deficient animals and most severe in Rlk/Itk double-deficient mice. These mice provide a useful mechanistic model for dissecting out the complex interactions of TCR signalling. Additionally, the mice are useful for evaluation of therapeutics directed at specific classes of diseases (Th1 or Th2) and the utility of potential global Tec kinase inhibitors.