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Agonist-Driven Development of CD4⁺CD25⁺Foxp3⁺ Regulatory T Cells Requires a Second Signal Mediated by Stat6¹

Vanesa Sanchez-Guajardo^*, Corinne Tanchot, John T. O’Malley, Mark H. Kaplan, Sylvie Garcia^* and Antonio A. Freitas^2,*

^* Unité de Biologie des Populations Lymphocytaires, Centre National de la Recherche Scientifique, Institut Pasteur, Paris, France; Institut National de la Santé et de la Recherche Médicale Unité 591, Institut Necker, Paris, France; and Department of Pediatrics, Microbiology and Immunology, HB Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202

The factors that induce Foxp3 expression and regulatory T (Treg) cell development remain unknown. In this study, we investigated the role of STAT4 and STAT6 in agonist-driven generation of Ag-specific Foxp3-expressing Treg cells. Our findings indicate that fully efficient induction of Foxp3 expression and development of Ag-specific Treg cells requires the synergistic action of two signals: a TCR-mediated signal and a second signal mediated by STAT6. Indeed, by comparing the development of wild-type and STAT4- and STAT6-deficient hemagglutinin-specific T cells in the presence of hemagglutinin Ag, we found that the absence of STAT6 impaired the generation of Ag-specific CD4⁺CD25⁺Foxp3⁺ cells. Moreover, in transgenic mice expressing a constitutively active form of STAT6, we found that the fraction of CD4⁺Foxp3⁺ cells exceeds that of control wild-type littermates. Overall these findings support a role for the STAT6 pathway in Treg cell development and maintenance.

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 Grant 642-02-0016 from the Danish Research Agency (to V.S.-G.) and by a study loan from El Consejo Nacional de Ciencia y Tecnologia. This work was also supported by the Association pour la Recherche contre le Cancer, Agence Nationale de la Recherche contre le SIDA, Association Française des Myopathies, Centre National de la Recherche Scientifique, Programmes Transversaux de Recherche from the Institiut Pasteur/Necker 114, and Public Health Service Awards from the National Institutes of Health (to M.H.K.).

² Address correspondence and reprint requests to Dr. Antonio A. Freitas, l’Unité Biologie des Populations Lymphocytaires, Institut Pasteur, 25 rue du Dr. Roux, 75015 Paris, France. E-mail address: afreitas{at}pasteur.fr

³ Abbreviations used in this paper: Treg, T regulatory; HA, hemagglutinin; TCR-HA, HA-specific TCR; LN, lymph node; BM, bone marrow; LDP, lymphopenia-driven proliferation; SP, single positive; WT, wild type.

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