title: Shaping of the autoreactive regulatory T cell repertoire by thymic cortical positive selection.
abstract: 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité 563, Toulouse, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Ribot
authors.forename: Geneviève
authors.initials: G
authors.lastname: Enault
authors.forename: Sylvie
authors.initials: S
authors.lastname: Pilipenko
authors.forename: Anne
authors.initials: A
authors.lastname: Huchenq
authors.forename: Maryline
authors.initials: M
authors.lastname: Calise
authors.forename: Denis
authors.initials: D
authors.lastname: Hudrisier
authors.forename: Paola
authors.initials: P
authors.lastname: Romagnoli
authors.forename: Joost P M
authors.initials: JP
authors.lastname: van Meerwijk
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000235:genetics / Q000276:immunology*; D054504:Precursor Cells, T-Lymphoid / Q000166:cytology / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*
chemical_list: D000949:Histocompatibility Antigens Class II; D008024:Ligands; D010455:Peptides; D011948:Receptors, Antigen, T-Cell