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Early TCR Expression and Aberrant T Cell Development in Mice with Endogenous Prerearranged T Cell Receptor Genes¹

Thomas Serwold^2,*, Konrad Hochedlinger, Matthew A. Inlay^*, Rudolf Jaenisch and Irving L. Weissman^2,*

^* Department of Pathology and Department of Developmental Biology, B259 Beckman Center, Stanford University School of Medicine, Stanford, CA 94305; Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Cancer Center and Center for Regenerative Medicine, Boston, MA 02114; and Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142

The factors that regulate the rate of production of T cells by the thymus remain incompletely defined. To test whether generation of functional T cell receptors limits the rate of thymic T cell export, we made use of a line of mice, LN3, that have endogenously prerearranged TCR genes. The prerearranged TCR genes were expressed abnormally early in hemopoietic development, indicating that RAG-mediated recombination, rather than transcription factor expression, is the key determinant of the initiation of robust TCR transcription. Thymic T cell export rates were similar between wild-type (wt) and LN3 mice, indicating that T cell maturation rates in these mice are determined by factors other than TCR gene rearrangement. In competitive bone marrow chimeras, however, LN3 thymocytes were out-competed by wt cells and failed to develop beyond the double-negative 4 stage. Furthermore, wt progenitors transplanted intrathymically into LN3 mice proliferated excessively, suggesting that increased proliferative signals in the LN3 thymus compensate for faulty T cell development driven by early TCR expression.

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 by Ruth L. Kirschstein National Research Service Award 1F 32 AI 58521 (to T.S.), by National Institutes of Health Grants R01-AI047458 and R01-AI047457 (to I.W.), and by National Institutes of Health Grants R37-CA84198, R01-HD0445022, and R01-CA87869 (to R.J.).

² Address correspondence and reprint requests to Dr. Thomas Serwold and Dr. Irving Weissman, Department of Pathology, B259 Beckman Center, Stanford University, Stanford, CA 94305. E-mail addresses: tserwold{at}stanford.edu or irv{at}stanford.edu

³ Abbreviations used in this paper: wt, wild type; DN, double negative; DP, double positive; NT, nuclear transfer; int, intermediate; CLP, common lymphoid progenitor; LT-HSC, long-term hemopoietic stem cell; ST-HSC, short-term HSC; MPP, multipotent progenitor.