Antigen-Specific Development of Mucosal Foxp3+RORγt+ T Cells from Regulatory T Cell Precursors

Foxp3⁺retinoic acid-related orphan receptor (ROR)γt⁺ T cells have recently been characterized as an immunoregulatory population highly enriched in the colon lamina propria. However, their developmental origin and relationship to RORγt^- regulatory T and Th17 cells remain unclear. In this study, we use a fixed TCRβ system to show that the TCR repertoire of the Foxp3⁺RORγt⁺ population is mostly distinct compared with other colonic T cell subsets. However, of these TCRs, a fraction is also found in the Th17 subset, suggesting that TCR repertoire overlap may contribute to the reported ability of Foxp3⁺RORγt⁺ cells to regulate Th17 immunity. Naive transgenic T cells expressing a Foxp3⁺RORγt⁺-restricted TCR first acquire a Foxp3⁺RORγt^- phenotype before coexpressing RORγt, suggesting that Foxp3⁺RORγt⁺ cell development can occur via an RORγt^- regulatory T cell intermediate.