Gene expression profiles of Lgr5-GFP high and Lgr5-GFP low cells in small intestines of Itgb7+/+ Lgr5-GFP mice and Itgb7-/- Lgr5-GFP mice

Intestinal stem cell (ISC) differentiation is regulated precisely by a niche in the crypt, where lymphocytes may interact with stem and transient amplifying (TA) cells. However, whether and how lymphocyte-stem/TA cell contact affects ISC differentiation is largely unknown. Here, we uncover a novel role of T cell-stem/TA cell contact in ISC fate decisions. We show that intestinal lymphocyte depletion results in skewed ISC differentiation in mice, which can be rescued by T cell transfer. Mechanistically, integrin aEß7 expressed on T cells binds to E-cadherin on ISCs and TA cells, triggering E-cadherin endocytosis and the consequent Wnt and Notch signaling alterations. Blocking aEß7—E-cadherin adhesion suppresses Wnt signaling and promotes Notch signaling in ISCs and TA cells, leading to defective ISC differentiation. Thus, aEß7+ T cells regulate ISC differentiation at single-cell level through cell-cell contact-mediated aEß7—E-cadherin adhesion signaling, highlighting a critical role of the T cell-stem/TA cell contact in maintaining intestinal homeostasis. Overall design: Gene expression profiles of Lgr5-GFP high (stem) and Lgr5-GFP low ( transient amplifying) cells in small intestines of Itgb7+/+ Lgr5-GFP mice and Itgb7-/- Lgr5-GFP mice