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

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.