T cell‐specific gene targeting reveals that α4 is required for early T cell development

Abstract

α4‐mediated signaling is involved in a variety of functions in mammalian cells. To determine whether this is true for immunocompetent cells, we generated mutant (Lck‐α4^–) micein which the α4 gene was deleted in a T cell‐specific manner using the Cre/loxP system. These mice showed impaired early T cell development. Thymi at most ages were small and their architecturewas disorganized. This defect was not due to increased thymocyte apoptosis but to decreased cell proliferation. T cell development was found to be severely arrested at the CD4/CD8 double‐negative 3stage and the thymus contained very few double‐positive or single‐positive (SP) mature thymocytes. The mutant thymocytes showed impaired proliferative responses to anti‐CD3 monoclonal antibody (mAb) stimulation or to the cytokines IL‐2, IL‐1 or TNF. In the spleen, the numbers of mature SP T cells were decreased and their proliferative responses to anti‐CD3 plus IL‐2 or to anti‐CD28 mAb were impaired. A severe impairment of CD3‐induced expression of CD25 was also observed. These data suggest that α4 plays a critical role in the proliferation of thymocytes, which is necessary for early T cell development.