title: Diversity of TCRs on natural Foxp3+ T cells in mice lacking Aire expression.
abstract: Medullary thymic epithelial cells expressing the Aire gene play a critical role in the induction of tolerance to tissue-specific Ags (TSAs). It was postulated that recognition of Aire-controlled TSAs by immature thymocytes results in the selection of natural CD4+Foxp3+ regulatory T cells (Tregs) and enriches this repertoire in self-reactive receptors, contributing to its vast diversity. In this study, we compared the TCRs on individual Tregs in Aire+ and Aire- mice expressing a miniature TCR repertoire (TCRmini) along with GFP driven by the Foxp3 promoter (Foxp3GFP). The Treg TCR repertoires in Aire+ and Aire- TCRminiFoxp3GFP mice were similar and more diverse than their repertoires on CD4+ Foxp3- thymocytes. Further, TCRs found on potentially self-reactive T cells, with an activated phenotype (CD4+Foxp3-CD62Llow) in Aire- TCRminiFoxp3GFP mice, appear distinct from TCRs found on Tregs in Aire+ TCRminiFoxp3GFP mice. Lastly, we found no evidence that TSAs presented by medullary thymic epithelial cells in Aire+TCRmini mice are often recognized as agonists by Treg-derived TCR hybridomas or CD4+CD25+ thymocytes, containing both natural Tregs and precursors. Thus, positive selection and self-reactivity of the global Treg repertoire are not controlled by Aire-dependent TSAs.
authors.affiliation: Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta, GA 30912, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Daniely
authors.forename: Joanna
authors.initials: J
authors.lastname: Kern
authors.forename: Anna
authors.initials: A
authors.lastname: Cebula
authors.forename: Leszek
authors.initials: L
authors.lastname: Ignatowicz
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D002469:Cell Separation; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014157:Transcription Factors / Q000172:deficiency / Q000276:immunology*; D000096927:AIRE Protein
chemical_list: D000941:Antigens; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D000096927:AIRE Protein