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Cutting Edge: Rescue of Pre-TCR but Not Mature TCR Signaling in Mice Expressing Membrane-Targeted SLP-76¹

Natalie A. Bezman^2,*, Rebecca G. Baker^2,*, Laurie E. Lenox, Martha S. Jordan and Gary A. Koretzky^3,*,,

^* Abramson Family Cancer Research Institute, Children’s Hospital of Philadelphia, Department of Pathology and Laboratory Medicine, and Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104

SLP-76 (Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa) organizes signaling from immunoreceptors, including the platelet collagen receptor, the pre-TCR, and the TCR, and is required for T cell development. In this study we examine a mouse in which wild-type SLP-76 is replaced with a mutant constitutively targeted to the cell membrane. Membrane-targeted SLP-76 (MTS) supports ITAM signaling in platelets and from the pre-TCR. Signaling from the mature TCR, however, is defective in MTS thymocytes, resulting in failed T cell differentiation. Defective thymic selection by MTS is not rescued by a SLP-76 mutant whose localization is restricted to the cytosol. Thus, fixed localization of SLP-76 reveals differential requirements for the subcellular localization of signaling complexes downstream of the pre-TCR vs mature TCR.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ N.A.B. was supported by a Predoctoral Fellowship from the Howard Hughes Medical Institute, R.G.B. by the American Heart Association, M.S.J. by the Arthritis Foundation and the National Institutes of Health, and G.A.K. by the National Institutes of Health and the Abramson Family Cancer Research Institute.

² N.A.B. and R.G.B. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Gary A. Koretzky, University of Pennsylvania, 415 Biomedical Research Building II/III, 421 Curie Boulevard., Philadelphia, PA 19104. E-mail address: Koretzky{at}mail.med.upenn.edu

⁴ Abbreviations used in this paper: DN, double negative; CVX, convulxin; DP, double positive; Gads, Grb-2-related adapter protein downstream of Shc; GPVI, glycoprotein VI; LAT, linker of activated T cells; MTS, membrane-targeted SLP-76; PLC, phospholipase C; PTK, protein tyrosine kinase; SLP-76, Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa; SP, single positive; WT, wild type.