Notch-1 signaling regulates intestinal epithelial barrier function, through interaction with CD4+ T cells, in mice and humans

Stephanie Dahan*, Keren M. Rabinowitz, Andrea P. Martin, M. Cecilia Berin, Jay C. Unkeless, Lloyd Mayer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


Background & Aims Interactions between lymphocytes and intestinal epithelial cells occur in the subepithelial space of the gastrointestinal tract. Normal human lamina propria lymphocytes (LPLs) induce differentiation of intestinal epithelial cells. The absence of LPLs in mice, such as in RAG1 -/- mice, results in defects in epithelial cell differentiation. We investigated the role of lymphoepithelial interactions in epithelial differentiation and barrier function. Methods We used adoptive transfer to determine if CD4+ T cells (CD4+CD62L +CD45RbHi and/or CD4+CD62L +CD45RbLo) could overcome permeability defect (quantified in Ussing chambers). Immunofluorescence staining was performed to determine expression of cleaved Notch-1, villin, and claudin 5 in colon samples from mice and humans. Caco-2 cells were infected with a lentivirus containing a specific Notch-1 or scrambled short hairpin RNA sequence. Tight junction assembly was analyzed by immunoblot and immunofluorescence analyses, and transepithelial resistance was monitored. Results Expression of cleaved Notch-1, villin, or claudin 5 was not detected in RAG1-/- colonocytes; their loss correlated with increased intestinal permeability. Transfer of CD45Rb Hi and/or CD45RbLo cells into RAG1-/- mice induced expression of cleaved Notch, villin, and claudin 5 in colonocytes and significantly reduced the permeability of the distal colon. Loss of Notch-1 expression in Caco-2 cells correlated with decreased transepithelial resistance and dysregulated expression and localization of tight junction proteins. Levels of cleaved Notch-1 were increased in colonic epithelium of patients with Crohn's disease. Conclusions LPLs promote mucosal barrier function, which is associated with activation of the Notch-1 signaling pathway. LPLs maintain intestinal homeostasis by inducing intestinal epithelial cell differentiation, polarization, and barrier function.

Original languageEnglish (US)
Pages (from-to)550-559
Number of pages10
Issue number2
StatePublished - Feb 2011


  • Immune System
  • Inflammatory Bowel Disease

ASJC Scopus subject areas

  • Gastroenterology
  • Hepatology


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