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

Gastroenterology. 2011 Dec;141(6):2109-18. doi: 10.1053/j.gastro.2011.09.015. Epub 2011 Sep 16.


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-10-producing 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Hypersensitivity, Delayed / immunology
  • Immune Tolerance / immunology*
  • Integrins / metabolism*
  • Interleukin-10 / metabolism
  • Intestinal Mucosa / immunology*
  • Mice
  • Mouth Mucosa / immunology
  • Receptors, CCR / metabolism*
  • T-Lymphocytes, Regulatory / immunology*


  • CC chemokine receptor 9
  • Integrins
  • Receptors, CCR
  • integrin alpha4beta7
  • Interleukin-10