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

Abstract

Foxp3 ⁺ regulatory T cells in peripheral tissues (pT _regs) are instrumental in limiting inflammatory responses to non-self antigens. Within the intestine, pT _regs are located primarily in the lamina propria, while 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 fashion, 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 intra-tissue specialization of anti-inflammatory T cells shaped by discrete niches of the intestine.