Tec family kinases modulate thresholds for thymocyte development and selection

Edward M. Schaeffer, Christine Broussard, Jayanta Debnath, Stacie Anderson, Daniel W. McVicar, Pamela L. Schwartzberg

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)987-1000
Number of pages14
JournalJournal of Experimental Medicine
Volume192
Issue number7
DOIs
StatePublished - Oct 2 2000
Externally publishedYes

Keywords

  • Gene-targeted mice
  • Itk
  • Rlk/Txk
  • Signal transduction
  • T cell receptor

ASJC Scopus subject areas

  • Immunology

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