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Anne M. Norment^*,||, Katherine A. Forbush^*,||, Nhan Nguyen^*,||, Marie Malissen^¶, and Roger M. Perlmutter^*,,,||

From the ^* Department of Immunology, Department of Biochemistry, Department of Medicine (Medical Genetics), and the ^|| Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195; and the ^¶ Centre d'Immunologie, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, de Marseille-Luminy, 13288 Marseille Cedex 9, France

An important checkpoint in early thymocyte development ensures that only thymocytes with an in-frame T cell receptor for antigen β (TCR-β) gene rearrangement will continue to mature. Proper assembly of the TCR-β chain into the pre-TCR complex delivers signals through the src-family protein tyrosine kinase p56^lck that stimulate thymocyte proliferation and differentiation to the CD4⁺CD8⁺ stage. However, the biochemical mechanisms governing p56^lck activation remain poorly understood. In more mature thymocytes, p56^lck is associated with the cytoplasmic domain of the TCR coreceptors CD4 and CD8, and cross-linking of CD4 leads to p56^lck activation. To study the effect of synchronously inducing p56^lck activation in immature CD4^–CD8^– thymocytes, we generated mice expressing a CD4 transgene in Rag2^–/– thymocytes. Remarkably, without further experimental manipulation, the CD4 transgene drives maturation of Rag2^–/– thymocytes in vivo. We show that this process is dependent upon the ability of the CD4 transgene to bind Lck and on the expression of MHC class II molecules. Together these results indicate that binding of MHC class II molecules to CD4 can deliver a biologically relevant, Lck-dependent activation signal to thymocytes in the absence of the TCR- or -β chain.

A.M. Norment is supported by a National Cancer Institute KO8 Clinical Investigator Award (no. K08 CA64448) and R.M. Perlmutter is an Investigator of the Howard Hughes Medical Institute. This work was supported in part by a grant from the National Institutes of Health (no. CA45682) to R.M. Perlmutter.

¹ Abbreviations used in this paper: DN, double-negative; DP, double-positive; ITAM, immunoreceptor tyrosine-based activation motifs.

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