21925467

PMC3222333

BACKGROUND & AIMS

Induction of oral immunological tolerance (OT) blocks proinflammatory responses to orally administered antigens; this approach 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 (TREG) cells, and IL-10−/− and IL-10Rβ−/− mice to examine the role of 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 cells and IL-10 were required to restore OT to CCR9−/− mice, indicating that homing and functional differentiation of IL-10-producing TREG cells 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 oral immunological tolerance in mice. Therapies designed to block gut-homing receptors might, under some conditions, interfere with normal tolerogenic mechanisms in the intestinal mucosa.

CDC Public Access

R00 AI075285-02/AI/NIAID NIH HHS/United States
P30 DK043351/DK/NIDDK NIH HHS/United States
NS38037/NS/NINDS NIH HHS/United States
AI435801/AI/NIAID NIH HHS/United States
P30 AR042689/AR/NIAMS NIH HHS/United States
DP2 OD006512-01/OD/NIH HHS/United States
R00 AI075285/AI/NIAID NIH HHS/United States
DP2 2009A054301/DP/NCCDPHP CDC HHS/United States
P01 NS038037/NS/NINDS NIH HHS/United States