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* Institute of Immunology, Biomedical Sciences Research Centre "Alexander Fleming", Vari, Greece; and
Department of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, NC 27710
HuR emerged as a posttranscriptional regulator of mRNAs involved in cellular control, stress, and immunity but its role in governing such responses remains elusive. In this study, we assessed HuR’s role in the staged progression of thymic T cell differentiation by means of its genetic ablation. Mice with an early deletion of HuR in thymocytes possess enlarged thymi but display a substantial loss of peripheral T cells. We show that this discordant phenotype related to specific defects in thymic cellular processes, which demonstrated HuR’s involvement in: 1) intrinsic checkpoint signals suppressing the cell cycle of immature thymocyte progenitors, 2) TCR and antigenic signals promoting the activation and positive selection of mature thymocytes, 3) antigenic and death-receptor signals promoting thymocyte deletion, and 4) chemokine signals driving the egress of postselection thymocytes to the periphery. The cellular consequences of HuR’s dysfunction were underlined by the aberrant expression of selective cell cycle regulators, TCR, and death-receptor signaling components. Our studies reveal the signal-dependent context of HuR’s cellular activities in thymocytes and its importance in the generation of a physiological T cell pool.
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 funding under the Sixth Research Framework Programme of the European Union, Project MUGEN NoE LSHG-CT-2005-005203 (www.mugen-noe.org) and the Hellenic Secretariat for Research and Technology Grants GSRT-PENED2003-394 and GSRT-PENED2003-264.
2 Address correspondence and reprint requests to Dr. Dimitris L. Kontoyiannis, Institute of Immunology, Biomedical Sciences Research Centre "Alexander Fleming", 34 Al. Fleming Street, 166 72 Vari, Greece. E-mail address: kontoyiannis{at}fleming.gr
3 Abbreviations used in this paper: DN, double negative; Cdk, cyclin-dependent kinase; DP, double positive; RBP, RNA-binding protein; R-IP, RNA-immunoprecipitation; RTE, recent thymic emigrant; SP, single positive.
4 The online version of this article contains supplemental material.
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