Terminal differentiation and persistence of effector regulatory T cells essential for preventing intestinal inflammation

Regulatory T (T_reg) cells are a specialized CD4⁺ T cell lineage with essential anti-inflammatory functions. Analysis of T_reg cell adaptations to non-lymphoid tissues that enable their specialized immunosuppressive and tissue-supportive functions raises questions about the underlying mechanisms of these adaptations and whether they represent stable differentiation or reversible activation states. Here, we characterize distinct colonic effector T_reg cell transcriptional programs. Attenuated T cell receptor (TCR) signaling and acquisition of substantial TCR-independent functionality seems to facilitate the terminal differentiation of a population of colonic effector T_reg cells that are distinguished by stable expression of the immunomodulatory cytokine IL-10. Functional studies show that this subset of effector T_reg cells, but not their expression of IL-10, is indispensable for colonic health. These findings identify core features of the terminal differentiation of effector T_reg cells in non-lymphoid tissues and their function.