Tissue adaptation of regulatory and intraepithelial CD4⁺ T cells controls gut inflammation

Foxp3⁺ regulatory T cells in peripheral tissues (pTregs) are instrumental in limiting inflammatory responses to nonself antigens. Within the intestine, pTregs are located primarily in the lamina propria, whereas intraepithelial CD4⁺ T cells (CD4IELs), which also exhibit anti-inflammatory properties and depend on similar environmental cues, reside in the epithelium. Using intravital microscopy, we show distinct cell dynamics of intestinal Tregs and CD4IELs. Upon migration to the epithelium, Tregs lose Foxp3 and convert to CD4IELs in a microbiota-dependent manner, an effect attributed to the loss of the transcription factor ThPOK. Finally, we demonstrate that pTregs and CD4IELs perform complementary roles in the regulation of intestinal inflammation. These results reveal intratissue specialization of anti-inflammatory T cells shaped by discrete niches of the intestine.