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Department of Immunology, Duke University Medical Center, Durham, NC 27710
Thymocytes undergoing TCR
gene rearrangements are maintained in a low or nonproliferating state during early T cell development. This block in cell cycle progression is not released until the expression of a functional pre-TCR, which is composed of a successfully rearranged TCR-chain and the Pre-T
-chain. The regulatory molecules responsible for the coordination of these differentiation and proliferation events are currently unknown. E2A and HEB are structurally and functionally related basic helix-loop-helix transcription factors involved in T cell development. To reveal the function of E2A and HEB through the stage of pre-TCR expression and alleviate functional compensation between E2A and HEB, we use a double-conditional knockout model. The simultaneous deletion of E2A and HEB in developing thymocytes leads to a severe developmental block before pre-TCR expression and a dramatic reduction of Pre-T expression. These developmentally arrested thymocytes exhibit increased proliferation in vivo and dramatic expansion ex vivo in response to IL-7 signaling. These results suggest that E2A and HEB are not only critical for T cell differentiation but also necessary to retain developing thymocytes in cell cycle arrest before pre-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 National Institutes of Health Grant R01 GM059638 (to Y.Z.).
2 Address correspondence and reprint requests to Dr. Yuan Zhuang, Duke University, Department of Immunology, DUMC 3010, Durham, NC 27710. E-mail address: yzhuang{at}duke.edu
3 Abbreviations used in this paper: DN, double negative; DP, double positive; SP, single positive; bHLH, basic helix-loop-helix; ISP, immature SP; DKO, double-conditional knockout; ES, embryonic stem; WT, wild type; fw, forward; rev, reverse; SKO, single knockout; LAT, linker for activation of T cell; CDKI, cyclin-dependent kinase inhibitor; 7AAD, 7-aminoactinomycin D; TC, Tricolor; del, deleted.
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