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

Foxp3 + regulatory T cells in peripheral tissues (pT regs ) are instrumental in limiting inflammatory responses to nonself antigens. Within the intestine, pT regs are located primarily in the lamina propria, whereas intraepithelial CD4 + T cells (CD4 IELs ), 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 T regs and CD4 IELs . Upon migration to the epithelium, T regs lose Foxp3 and convert to CD4 IELs in a microbiota-dependent manner, an effect attributed to the loss of the transcription factor ThPOK. Finally, we demonstrate that pT regs and CD4 IELs 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.