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Precursor Thymocyte Proliferation and Differentiation Are Controlled by Signals Unrelated to the Pre-TCR¹

Howard T. Petrie^2,*,, Michelle Tourigny^3,*,, Douglas B. Burtrum^* and Ferenc Livak

^* Immunology Program, Memorial Sloan-Kettering Cancer Center, and Joan and Sanford Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021; and Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201

In-frame rearrangement of the TCR-ß locus and expression of the pre-TCR are compulsory for the production of CD4⁺8⁺ thymocytes from CD4^-8^- precursors. Signals delivered via the pre-TCR are thought to induce the differentiation process as well as the extensive proliferation that accompanies this transition. However, it is equally possible that pre-TCR expression is required for the success of this transition, but does not play a direct role in the inductive process. In the present manuscript we examine this possibility using a variety of normal and genetically modified mouse models. Our evidence shows that differentiation and mitogenesis can both occur independently of pre-TCR expression. However, these processes are absolutely dependent on the presence of normal thymic architecture and cellular composition. These findings are consistent with a checkpoint role for the pre-TCR in regulating the divergence of survival and cell death fates at the CD4^-8^- to CD4⁺8⁺ transition. Further, our data suggest that precursor thymocyte differentiation is induced by other, probably ubiquitous, mechanisms that require the presence of normal thymic cellularity, composition, and architecture.

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