Tec Family Kinases Modulate Thresholds for Thymocyte Development and Selection

doi:10.1084/jem.192.7.987

Published online 2 October 2000.

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© The Rockefeller University Press, 0022-1007/2000/10/987/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 7, October 2, 2000 987-1000

Original Article

Tec Family Kinases Modulate Thresholds for Thymocyte Development and Selection

Edward M. Schaeffer^a^,c, Christine Broussard^a, Jayanta Debnath^a, Stacie Anderson^a, Daniel W. McVicar^b, and Pamela L. Schwartzberg^a

^a National Human Genome Research Institute, Frederick Cancer Research and Development Center, National Institutes of Health, Frederick, Maryland 21702
^b National Cancer Institute, Frederick Cancer Research and Development Center, National Institutes of Health, Frederick, Maryland 21702
^c Department of Pathology, University of Chicago, Chicago, Illinois 60637
Bldg. 49/4A38, 49 Convent Dr., National Human Genome Research Institute, NIH, Bethesda, MD 20892-4472.301-402-2170301-435-1906

Tec family kinases are implicated in T cell receptor (TCR) signaling,and combined mutation of inducible T cell kinase (Itk) and restinglymphocyte kinase (Rlk)/Txk in mice dramatically impairs matureT cell function. Nonetheless, mutation of these kinases stillpermits T cell development. While itk^–^/– mice exhibitmild reductions in T cells with decreased CD4/CD8 cell ratios,rlk^–^/–itk^–^/– mice have improved totalT cell numbers yet maintain decreased CD4/CD8 ratios. UsingTCR transgenics and an in vitro thymocyte deletion model, wedemonstrate that mutation of Tec kinases causes graded defectsin thymocyte selection, leading to a switch from negative topositive selection in rlk^–^/–itk^–^/– animals.The reduction in both positive and negative selection and decreasedCD4/CD8 ratios correlates with decreased biochemical parametersof TCR signaling, specifically defects in capacitive Ca²⁺ influxand activation of the mitogen-activated kinases extracellularsignal–regulated kinase 1 and 2. Thus, Tec kinases influencecell fate determination by modulating TCR signaling, leadingto altered thresholds for thymocyte selection. These resultsprovide support for a quantitative model for thymic developmentand provide evidence that defects in negative selection cansubstantially alter thymic cellularity.

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

Abbreviations used in this paper: DP, double-positive; ERK,extracellular signal–regulated kinase; GRB, growth factorreceptor–bound protein; HSA, human serum albumin; LAT,linker of activated T cells; MAP, mitogen-activated protein;PI, propidium iodide; PLC, phospholipase C; SP, single-positive;WT, wild-type; XLA, X-linked agammaglobulinemia.

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