Gut-tropic T cells that express integrin α4β7 and CCR9 Are required for induction of oral immune tolerance in mice

Barbara Cassani, Eduardo J. Villablanca, Francisco J. Quintana, Paul E. Love, Adam Lacy-Hulbert, William S. Blaner, Tim Sparwasser, Scott B. Snapper, Howard L. Weiner, J. Rodrigo Mora

Research output: Contribution to journalArticle

Abstract

Background & Aims: Induction of oral immune tolerance (OT) blocks proinflammatory responses to orally administered antigens and might be used to treat autoimmune conditions. We investigated whether gut-tropic T cells that express the integrin α4β7 and the chemokine receptor CCR9 are required for OT. Methods: Skin delayed-type hypersensitivity and experimental autoimmune encephalomyelitis were used to monitor OT in mice. To assess the role of receptors that mediate localization of lymphocytes to the gut (gut-homing receptors) in induction of OT, we studied CCR9 -/- and β7 -/- mice and also blocked the α4β7 ligand MAdCAM-1 in wild-type mice. We used DEREG and Scurfy mice to assess the role of Foxp3 + regulatory T cells (Treg) and IL-10 -/- and IL-10Rβ -/- mice to examine the role of interleukin (IL)-10 in induction of OT. Results: OT could not be induced in CCR9 -/- or β7 -/- mice, or when MAdCAM-1 was blocked in wild-type mice, indicating that gut-homing receptors are required for oral tolerization. Consistent with the role of all-trans retinoic acid in inducing gut-homing T cells, OT could not be induced in mice depleted of vitamin A. OT was rescued in CCR9 -/- mice following adoptive transfer of wild-type T cells, but not CCR9 -/- or β7 -/- T cells. Gut-homing T cells are therefore necessary and sufficient to induce OT. Wild-type Treg and IL-10 were required to restore OT to CCR9 -/- mice, indicating that homing and functional differentiation of IL-10producing Treg in the gut is required for OT. Conversely, transfer of CCR9 -/- or β7 -/- T cells to wild-type mice partially inhibited OT. Conclusions: Expression of CCR9 and α4β7 on T cells and their subsequent localization to the gut is required for induction of OT in mice. Therapies designed to block gut-homing receptors might, under some conditions, interfere with normal tolerogenic mechanisms in the intestinal mucosa.

Original languageEnglish
Pages (from-to)2109-2118
Number of pages10
JournalGastroenterology
Volume141
Issue number6
DOIs
Publication statusPublished - Dec 2011

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Keywords

  • Allergy
  • Autoimmunity
  • Immune Regulation
  • Intestine
  • Peyer's Patch

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Cassani, B., Villablanca, E. J., Quintana, F. J., Love, P. E., Lacy-Hulbert, A., Blaner, W. S., Sparwasser, T., Snapper, S. B., Weiner, H. L., & Mora, J. R. (2011). Gut-tropic T cells that express integrin α4β7 and CCR9 Are required for induction of oral immune tolerance in mice. Gastroenterology, 141(6), 2109-2118. https://doi.org/10.1053/j.gastro.2011.09.015