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Shaping of the Autoreactive Regulatory T Cell Repertoire by Thymic Cortical Positive Selection¹

Julie Ribot^*, Geneviève Enault^*, Sylvie Pilipenko, Anne Huchenq, Maryline Calise, Denis Hudrisier^,, Paola Romagnoli^* and Joost P. M. van Meerwijk^2,*,,¶

^* Institut National de la Santé et de la Recherche Médicale Unité 563, Toulouse, France; Université Toulouse III Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan, and Institut Fédératif de Recherche (IFR) 30, Institut Claude de Preval, Toulouse, France; Transgenic Mouse Facility, IFR 30, Institut Claude de Preval, Toulouse, France; Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique, Toulouse, France; Faculty of Life Sciences University Paul Sabatier, Toulouse, France; and ^¶ Institut Universitaire de France, Paris, France

The main function of regulatory T lymphocytes is to keep autoimmune responses at bay. Accordingly, it has been firmly established that the repertoire of CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Tregs) is enriched in autospecific cells. Differences in thymic-positive and/or -negative selection may account for selection of the qualitatively distinct regulatory and conventional T cell (Tconv) repertoires. It has previously been shown that precursors for Tregs are less sensitive to negative selection than Tconv precursors. Studies with TCR/ligand doubly transgenic mice suggested that an agonist ligand might induce positive selection of Treg (but not Tconv) cells. However, massive deletion of Tconv (but not Treg) cell precursors observed in these mice renders interpretation of such data problematic and a potential role for positive selection in generation of the autospecific Treg repertoire has remained therefore incompletely understood. To study this important unresolved issue and circumvent use of TCR/ligand-transgenic mice, we have developed transgenic mice expressing a single MHC class II/peptide ligand on positively selecting thymic cortical epithelial cells. We found that functional Treg (but not Tconv) cells specific for the single ligand were preferentially selected from the naturally diverse repertoire of immature precursors. Our data therefore demonstrate that thymic cortical positive selection of regulatory and Tconv precursors is governed by distinct rules and that it plays an important role in shaping the autoreactive Treg repertoire.

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 a grant from the European Community awarded to the EuroThymaide Consortium (Contract No. LSHB-CT-2003-503410).

² Address correspondence and reprint requests to Dr. Joost P. M. van Meerwijk, Institut National de la Santé et de la Recherche Médicale Unité 563, BP 3028, 31024 Toulouse Cedex 3, France. E-mail address: Joost.van-Meerwijk{at}toulouse.inserm.fr

³ Abbreviations used in this paper: Treg, regulatory T cell; Tconv, conventional T cell; TEC, thymic epithelial cell; cTEC, cortical TEC; mTEC, medullary TEC; bCII, bovine collagen type II; SP, single positive; LDA, limiting dilution analysis.

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