ALTERED T-CELL RECEPTOR SIGNALING AND DISRUPTED T-CELL DEVELOPMENT INMICE LACKING ITK

Itk is a T cell protein tyrosine kinase (PTK) that, along with Btk and Tee, belongs to a family of cytoplasmic PTKs with N-terminal pleckstr in homology domains. Btk plays a critical role in B lymphocyte develop ment. To determine whether Itk has an analogous role in T lymphocytes, we used gene targeting to prepare mice lacking expression of Itk. Suc h animals had decreased numbers of mature thymocytes, an effect most c learly observed in mice expressing T cell receptor (TCR) transgenes. M ature T cells from Itk-deficient mice had reduced proliferative respon ses to allogeneic MHC stimulation and to anti-TCR cross-linking, but r esponded normally to stimulation with phorbol ester plus ionomycin or with IL-2. These results provide genetic evidence that Itk is involved in T cell development and also suggest that Itk has an important role in proximal events in TCR-mediated signaling pathways.