Correction of Defective T-Regulatory Cells From Patients With Crohn's Disease by Ex Vivo Ligation of Retinoic Acid Receptor-α

Gastroenterology. 2019 May;156(6):1775-1787. doi: 10.1053/j.gastro.2019.01.025. Epub 2019 Jan 30.


Background & aims: Crohn's disease (CD) is characterized by an imbalance of effector and regulatory T cells in the intestinal mucosa. The efficacy of anti-adhesion therapies led us to investigate whether impaired trafficking of T-regulatory (Treg) cells contributes to the pathogenesis of CD. We also investigated whether proper function could be restored to Treg cells by ex vivo expansion in the presence of factors that activate their regulatory activities.

Methods: We measured levels of the integrin α4β7 on Treg cells isolated from peripheral blood or lamina propria of patients with CD and healthy individuals (controls). Treg cells were expanded ex vivo and incubated with rapamycin with or without agonists of the retinoic acid receptor-α (RARA), and their gene expression profiles were analyzed. We also studied the cells in cytokine challenge, suppression, and flow chamber assays and in SCID mice with human intestinal xenografts.

Results: We found that Treg cells from patients with CD express lower levels of the integrin α4β7 than Treg cells from control patients. The pathway that regulates the expression of integrin subunit α is induced by retinoic acid (RA). Treg cells from patients with CD incubated with rapamycin and an agonist of RARA (RAR568) expressed high levels of integrin α4β7, as well as CD62L and FOXP3, compared with cells incubated with rapamycin or rapamycin and all-trans retinoic acid. These Treg cells had increased suppressive activities in assays and migrated under conditions of shear flow; they did not produce inflammatory cytokines, and RAR568 had no effect on cell stability or lineage commitment. Fluorescently labeled Treg cells incubated with RAR568 were significantly more likely to traffic to intestinal xenografts than Treg cells expanded in control medium.

Conclusions: Treg cells from patients with CD express lower levels of the integrin α4β7 than Treg cells from control patients. Incubation of patients' ex vivo expanded Treg cells with rapamycin and an RARA agonist induced expression of α4β7 and had suppressive and migratory activities in culture and in intestinal xenografts in mice. These cells might be developed for treatment of CD., Number: NCT03185000.

Keywords: Cell Therapy; IBD; Immune Regulation; Tissue Engineering.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antineoplastic Agents / pharmacology
  • Case-Control Studies
  • Cell Culture Techniques
  • Cell Movement / drug effects
  • Cells, Cultured
  • Crohn Disease / immunology*
  • Female
  • Forkhead Transcription Factors / metabolism
  • Gene Expression / drug effects
  • Heterografts
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Integrins / genetics
  • Integrins / metabolism*
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / transplantation
  • L-Selectin / metabolism
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, SCID
  • Middle Aged
  • Organic Chemicals / pharmacology
  • Retinoic Acid Receptor alpha / agonists*
  • Sirolimus / pharmacology
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*
  • Transcriptome / drug effects
  • Tretinoin / pharmacology


  • Antineoplastic Agents
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Immunosuppressive Agents
  • Integrins
  • Organic Chemicals
  • RAR568
  • RARA protein, human
  • Retinoic Acid Receptor alpha
  • integrin alpha4beta7
  • L-Selectin
  • Tretinoin
  • Sirolimus

Associated data