title: Gut-tropic T cells that express integrin α4β7 and CCR9 are required for induction of oral immune tolerance in mice.
abstract: OBJECTIVE
  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.
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cassani
authors.forename: Eduardo J
authors.initials: EJ
authors.lastname: Villablanca
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Quintana
authors.forename: Paul E
authors.initials: PE
authors.lastname: Love
authors.forename: Adam
authors.initials: A
authors.lastname: Lacy-Hulbert
authors.forename: William S
authors.initials: WS
authors.lastname: Blaner
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.forename: Scott B
authors.initials: SB
authors.lastname: Snapper
authors.forename: Howard L
authors.initials: HL
authors.lastname: Weiner
authors.forename: J Rodrigo
authors.initials: JR
authors.lastname: Mora
mesh_terms: D000818:Animals; D002465:Cell Movement; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D016023:Integrins / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology*; D051379:Mice; D009061:Mouth Mucosa / Q000276:immunology; D054388:Receptors, CCR / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C119309:CC chemokine receptor 9; D016023:Integrins; D054388:Receptors, CCR; C071777:integrin alpha4beta7; D016753:Interleukin-10