GSE135316
Integrin aEß7+ T cells direct intestinal stem cell fate decision via adhesive signaling
Intestinal stem cells (ISCs) maintain gut homeostasis by differentiating into different epithelial cell types, which is precisely regulated by a niche of accessory cell types. In the niche, lymphocytes may interact with stem and transient amplifying (TA) cells in the intestinal crypts. However, it is unknown whether and how the lymphocyte- stem/TA cell contacts affect ISC differentiation. Here we discover and mechanistically dissect the role of T cell-stem/TA cell contacts in ISC fate decision. We found T cells are often seen in contact with ISCs and TA cells in the small intestinal crypts, whereas B cell-stem/TA cell interaction was hardly observed. Using single-cell RNA sequencing and immunostaining, we showed that depletion of intestinal lymphocytes resulted in aberrant ISC differentiation in mice, with decreased Paneth and goblet cells, increased enteroendocrine cells and impaired enterocyte maturation. Transferring T cells but not B cells into those mice efficiently restored normal ISC differentiation. Mechanistically, integrin aEß7 on T cells binds to E-cadherin on ISCs and TA cells. Blocking this adhesion suppressed Wnt signaling in ISCs and TA cells and promoted Notch signaling in TA cells, leading to defective ISC differentiation. In vitro study using purified aEß7 protein showed consistent effects on the intestinal organoid differentiation. Taken together, our study reveals that the gut-resident integrin aEb7+ T cells regulate the ISC differentiation through adhesion between aEß7 on T cells and E-cadherin on ISCs and TA cells. The aEß7-E-cadherin adhesive signaling is critical for the fate decision of ISCs and the maintenance of intestinal homeostasis. Overall design: Using single-cell RNA-seq of  enriched crypt epithelial cells from C57BL/6J WT and integrin ß7 knock out (Itgb7-/-) mice small intestines in triplicate, we found that lack of intestinal lymphocytes resulted in aberrant ISC differentiation in mice, with decreased Paneth and goblet cells, increased enteroendocrine cells and impaired enterocyte maturation.