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A CD8/Lck Transgene Is Able to Drive Thymocyte Differentiation¹

Ruben C. Fragoso^2,*, Saiju Pyarajan^2,*,, Hanna Yoko Irie^* and Steven J. Burakoff^3,*,

^* Dana-Farber Cancer Institute, Department of Pediatric Oncology, Harvard Medical School, Boston, MA 02115; and Skirball Institute of Biomolecular Medicine and Department of Pathology, New York University Cancer Institute, New York University School of Medicine, New York 10016

Efficient development of thymocytes requires participation of a CD8 or CD4 coreceptor in the TCR:MHC interaction. Both CD8 and CD4 coreceptor cytoplasmic domains associate with Lck. In this study, we attempted to delineate the role of CD8-associated Lck in driving CD8 single positive (SP) thymocyte development. We used a chimeric molecule encoding the extracellular and transmembrane domains of CD8 fused to full-length Lck. In mice deficient for CD8 and transgenic for 2C, a MHC class I-restricted TCR, robust reconstitution of CD8 SP thymocytes occurred both centrally and peripherally. The reconstituted CD8 SP population was phenotypically and functionally comparable to 2C wild-type counterparts expressing endogenous CD8. A CD8/Lck kinase-dead chimera also resulted in reconstitution of CD8 SP thymocytes. Our results suggest that CD8-associated Lck is sufficient to drive CD8 SP thymocyte development. Furthermore, this CD8 SP development may not necessarily depend on Lck kinase activity.

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 This work was supported in part by National Institutes of Health Grant AI 17258 (to S.J.B.).

² R.C.F. and S.P. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Steven J. Burakoff, 540 First Avenue, Floor 5/Laboratory No. 1, Skirball Institute of Biomolecular Medicine, New York, NY 10016. E-mail address: burakoff{at}saturn.med.nyu.edu

⁴ Abbreviations used in this paper: SP, single positive; DN, double negative; DP, double positive; LAT, linker for activation of T cells; MFI, median fluorescence intensity; SH, Src homology.