Diversity of TCRs on Natural Foxp3+ T Cells in Mice Lacking Aire Expression

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 (Foxp3(GFP)). The Treg TCR repertoires in Aire(+) and Aire(-) TCR(mini)Foxp3(GFP) mice were similar and more diverse than their repertoires on CD4(+) Foxp3(-) thymocytes. Further, TCRs found on potentially selfreactive T cells, with an activated phenotype (CD4(+)Foxp3(-)CD62L(low)) in Aire(-) TCR(mini)Foxp3(GFP) mice, appear distinct from TCRs found on Tregs in Aire(+) TCR(mini)Foxp3(GFP) mice. Lastly, we found no evidence that TSAs presented by medullary thymic epithelial cells in Aire(+) TCR mini 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. The Journal of Immunology, 2010, 184: 6865- 6873.