Tec family kinases modulate thresholds for thymocyte development and selection

Tec family kinases are implicated in T cell receptor (TCR) signaling, and c ombined mutation of inducible T cell kinase (Itk) and resting lymphocyte ki nase (Rlk)/Txk in mice dramatically impairs mature T cell function. Nonethe less, mutation of these kinases still permits T cell development. While itk (-/-) mice exhibit mild reductions in T cells with decreased CD4/CD8 cell r atios, rlk(-/-)itk(-/-) mice have improved total T cell numbers yet maintai n decreased CD4/CD8 ratios. Using TCR transgenics and an in vitro thymocyte deletion model, we demonstrate that mutation of Tec kinases causes graded defects in thymocyte selection, leading to a switch from negative to positi ve selection in rlk(-/-)itk(-/-) animals. The reduction in both positive an d negative selection and decreased CD4/CD8 ratios con-elates with decreased biochemical parameters of TCR signaling, specifically defects in capacitiv e Ca2+ influx and activation of the mitogen-activated kinases extracellular signal-regulated kinase 1 and 2. Thus, Tec kinases influence cell fate det ermination by modulating TCR signaling, leading to altered thresholds for t hymocyte selection. These results provide support for a quantitative model for thymic development and provide evidence that defects in negative select ion can substantially alter thymic cellularity.