Antigen-specific development of mucosal Foxp3⁺RORgt⁺ T cells from regulatory T cell precursors

Foxp 3⁺ retinoic acid-related orphan receptor (ROR)gt⁺ T cells have recently been characterized as an immunoregulatory population highly enriched in the colon lamina propria. However, their developmental origin and relationship to RORgt² regulatory T and Th17 cells remain unclear. In this study, we use a fixed TCRb system to show that the TCR repertoire of the Foxp3⁺RORgt⁺ 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⁺RORgt⁺ cells to regulate Th17 immunity. Naive transgenic T cells expressing a Foxp3⁺RORgt⁺-restricted TCR first acquire a Foxp3⁺RORgt² phenotype before coexpressing RORgt, suggesting that Foxp3⁺RORgt⁺ cell development can occur via an RORgt² regulatory T cell intermediate.