The Journal of Experimental Medicine
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Published online 26 September 2005 doi:10.1084/jem.20051128
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 7, 893-900
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BRIEF DEFINITIVE REPORT

 Conditional deletion reveals a cell-autonomous requirement of SLP-76 for thymocyte selection

Jonathan S. Maltzman1,3, Lisa Kovoor3, James L. Clements4, and Gary A. Koretzky1,2,3

1 Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
2 Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
3 Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
4 Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263

CORRESPONDENCE Gary A. Koretzky: koretzky{at}mail.med.upenn.edu

The SH2 domain containing leukocyte phosphoprotein of 76 kD (SLP-76) is critical for pre-TCR–mediated maturation to the CD4+CD8+ double positive (DP) stage in the thymus. The absolute block in SLP-76null mice at the CD4–CD8–CD44–CD25+ (double-negative 3, DN3) stage has hindered our understanding of the role of this adaptor in {alpha}ß TCR-mediated signal transduction in primary thymocytes and peripheral T lymphocytes. To evaluate the requirements for SLP-76 in these events, we used a cre-loxP approach to generate mice that conditionally delete SLP-76 after the DN3 checkpoint. These mice develop DP thymocytes that express the {alpha}ß TCR on the surface, but lack SLP-76 at the genomic DNA and protein levels. The DP compartment has reduced cellularity in young mice and fails to undergo positive selection to CD4+ or CD8+ single positive (SP) cells in vivo or activation-induced cell death in vitro. A small number of CD4+SP thymocytes are generated, but these cells fail to flux calcium in response to an {alpha}ß TCR-generated signal. Peripheral T cells are reduced in number, lack SLP-76 protein, and have an abnormal surface phenotype. These studies show for the first time that SLP-76 is required for signal transduction through the mature {alpha}ß TCR in primary cells of the T lineage.


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