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Gads^–/– Mice Reveal Functionally Distinct Subsets of TCR⁺ CD4^–CD8^– Double-Negative Thymocytes¹

Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, Kansas City, KS 66160

TCR expression in CD4^–CD8^– double-negative (DN) thymocytes induces signaling pathways that promote survival and proliferation, as well as differentiation into CD4⁺CD8⁺ double-positive thymocytes. The signaling pathways that regulate survival, proliferation, and differentiation remain unclear. We used Gads-deficient mice to investigate the signaling pathways that regulate these cell fates. During this investigation, we focused on TCR⁺ DN thymocytes and found that there are at least three functionally distinct subsets of TCR⁺ DN thymocytes: TCR⁺ DN3E, TCR⁺ DN3L, and TCR⁺ DN4. Survival and proliferation of TCR⁺ DN3E were independent of Gads, but survival and proliferation of TCR⁺ DN3L cells were Gads dependent. Likewise, expression of Bcl-2 in TCR⁺ DN3E cells was Gads independent, but Gads was necessary for Bcl-2 expression in TCR⁺ DN3L cells. Bcl-2 expression was not dependent on Gads in TCR⁺ DN4 cells, but proliferation of TCR⁺ DN4 cells was Gads dependent. Gads was not required for the differentiation of DN thymocytes into DP thymocytes. In fact, Gads^–/– DN3E cells differentiated into DP thymocytes more readily than wild-type cells. We conclude that signaling pathways required to initiate TCR-induced survival and proliferation are distinct from the pathways that maintain survival and proliferation. Furthermore, signaling pathways that promote survival and proliferation may slow differentiation.

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 P20 RR016443 from the Centers of Biomedical Research Excellence Program of the National Center for Research Resources.

² Address correspondence and reprint requests to Dr. Thomas M. Yankee, Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, 3901 Rainbow Boulevard, 3025 Wahl Hall West, Mail Stop 3029 Kansas City, KS 66160. E-mail address: tyankee{at}kumc.edu

³ Abbreviations used in this paper: DN, double negative; DP, double positive; SP, single positive; PTK, protein tyrosine kinase; LAT, linker for activation of T cells; SH, Src homology; SLP-76, SH2 domain-containing leukocyte protein of 76-kDa; RT, room temperature; DAPI, 4',6-diamidino-2-phenylindole; EMA, ethidium monoazide bromide; MFI, mean fluorescence intensity.

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