Original Article

Tec Family Kinases Modulate Thresholds for Thymocyte Development and Selection

Correspondence to: Pamela L. Schwartzberg, Bldg. 49/4A38, 49 Convent Dr., National Human Genome Research Institute, NIH, Bethesda, MD 20892-4472. Tel:301-435-1906 Fax:301-402-2170

Tec family kinases are implicated in T cell receptor (TCR) signaling, and combined mutation of inducible T cell kinase (Itk) and resting lymphocyte kinase (Rlk)/Txk in mice dramatically impairs mature T cell function. Nonetheless, mutation of these kinases still permits T cell development. While itk^-/- mice exhibit mild reductions in T cells with decreased CD4/CD8 cell ratios, rlk^-/-itk^-/- mice have improved total T cell numbers yet maintain 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 positive selection in rlk^-/-itk^-/- animals. The reduction in both positive and negative selection and decreased CD4/CD8 ratios correlates with decreased biochemical parameters of TCR signaling, specifically defects in capacitive Ca²⁺ influx and activation of the mitogen-activated kinases extracellular signal–regulated kinase 1 and 2. Thus, Tec kinases influence cell fate determination by modulating TCR signaling, leading to altered thresholds for thymocyte selection. These results provide support for a quantitative model for thymic development and provide evidence that defects in negative selection can substantially alter thymic cellularity.

Key Words: gene-targeted mice, signal transduction, Itk, Rlk/Txk, T cell receptor

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