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

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...

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Bibliographic Details
Published in:	The Journal of experimental medicine Vol. 202; no. 7; pp. 893 - 900
Main Authors:	Maltzman, Jonathan S, Kovoor, Lisa, Clements, James L, Koretzky, Gary A
Format:	Journal Article
Language:	English
Published:	United States The Rockefeller University Press 03-10-2005
Subjects:	Adaptor Proteins, Signal Transducing Animals Blotting, Southern Blotting, Western Brief Definitive Report Calcium - metabolism Cell Differentiation - immunology Cell Lineage - immunology Female Flow Cytometry Gene Deletion Mice Mice, Inbred C57BL Phosphoproteins - genetics Signal Transduction - immunology Stem Cells - immunology T-Lymphocyte Subsets - cytology T-Lymphocyte Subsets - immunology Thymus Gland - cytology
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Summary:	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 alphabeta 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 alphabeta 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 alphabeta 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 alphabeta TCR in primary cells of the T lineage.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 CORRESPONDENCE Gary A. Koretzky: koretzky@mail.med.upenn.edu
ISSN:	0022-1007 1540-9538 1892-1007
DOI:	10.1084/jem.20051128