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Cutting Edge: CD4-Independent Development of Functional FoxP3⁺ Regulatory T Cells¹

Céline Blache^*, Sahil Adriouch^*, Sébastien Calbo^*, Laurent Drouot^*, Sophie Dulauroy^2,, Christophe Arnoult^*, Stéphanie Le Corre^*,, Adrien Six^3,, Michel Seman^* and Olivier Boyer^4,*,

^* INSERM, Unité 905, Rouen, France; University of Rouen, Institut Fédératif de Recherches Multidisciplinaires sur les Peptides, Institute for Biomedical Research, Rouen, France; Rouen University Hospital, Department of Immunology, Rouen, France; Université Pierre et Marie Curie-Paris 6, Centre National de la Recherche Scientifique Unité de Recherche Associée 1961, Immunophysiopathologie Infectieuse, Institut Pasteur, Paris, France

The CD4 coreceptor is mandatory for the differentiation and function of conventional MHC class II-restricted T cells, but little is known about its contribution in regulatory T cells (Tregs). We thus investigated the Treg compartment in mice lacking CD4. CD3⁺CD8^–FoxP3⁺ cells were readily detected in the periphery of CD4^–/– mice, where their percentages were even increased as compared with wild-type animals. These cells had a classical CD25⁺CD152⁺GITR⁺ Treg phenotype, were enriched in memory-type Tregs, and displayed a diversified TCR repertoire. Functionally, CD4^–/– Tregs were equally as suppressive as CD4^+/+ Tregs in vitro as well as in vivo. Hence, the CD4 coreceptor is dispensable for the generation and function of FoxP3⁺ Tregs. Furthermore, CD3⁺CD8^–FoxP3⁺ Tregs were also found to develop in the absence of both CD4 and MHC-II molecules, demonstrating that the generation of Tregs can occur independently of MHC-II recognition.

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 funded in part by INSERM, Institut Pasteur, Fondation pour la Recherche Médicale, and Région Haute-Normandie.

² Current address: Développement des Tissus Lymphoïdes, Institut Pasteur, Paris, France.

³ Current address: Unité Mixte de Recherche 7211 Centre National de la Recherche Scientifique and Université Pierre et Marie Curie, I2D3 Team "Integrative Immunology," Bâtiment CERVI, 83 Boulevard de l’Hôpital, F-75013 Paris, France.

⁴ Address correspondence and reprint requests to Dr. Olivier Boyer, INSERM, Unité 905, 22 Boulevard Gambetta, F-76000 Rouen, France. E-mail address: olivier.boyer{at}chu-rouen.fr

⁵ Abbreviations used in this paper: Treg, regulatory T cell; IBD, inflammatory bowel disease; LN, lymph node; Tconv, conventional T cell.

⁶ The online version of this article contains supplemental material.