Abstract

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 αEβ7 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 αEβ7−E-cadherin adhesion suppresses Wnt signaling and promotes Notch signaling in ISCs and TA cells, leading to defective ISC differentiation. Thus, αEβ7 + T cells regulate ISC differentiation at single-cell level through cell–cell contact-mediated αEβ7−E-cadherin adhesion signaling, highlighting a critical role of the T cell–stem/TA cell contact in maintaining intestinal homeostasis.