Epithelial E-cadherin and its receptor KLRG1 limit the accumulation of Treg in the gut

Intestinal immune responses rely on the tight control of Foxp3⁺ regulatory T cells (Treg). However, which tissue-specific factors control intestinal Treg populations is not fully understood. Effector Treg, especially gut Treg, express high levels of CD103 and KLRG1, the receptors for the epithelial molecule E-cadherin, suggesting a role for E-cadherin on intestinal Treg.  To bypass the lethal effects of intestinal E-cadherin depletion, we use here a model of E-cadherin replacement by N-cadherin. This replacement allows for postnatal mouse survival despite intestinal inflammation. In this model we found a strong accumulation of KLRG1⁺ Treg in the intestine. The accumulating Treg had a Foxp3⁺ GATA3^int effector Treg phenotype, suggesting that the absence of E-cadherin favors the expansion of this specific Treg subset. We then reciprocally analyzed the effects of KLRG1 on Treg.  In vitro assays showed that KLRG1 ligation reduces Treg response to TCR signals and limits Treg survival in vitro. Analysis of KLRG1-deficient mice showed that lack of KLRG1 confers a competitive advantage on Treg in the gut, but not in lymphoid organs, supporting a direct role for E-cadherin in modulating KLRG1⁺ Treg. Our findings point to a novel level of interaction between epithelial cells and lymphocytes in shaping gut immunity.