Gut-Tropic T Cells That Express Integrin α4β7 and CCR9 Are Required for Induction of Oral Immune Tolerance in Mice

被引：167

作者：

Cassani, Barbara ^{[1
]}

Villablanca, Eduardo J. ^{[1
]}

Quintana, Francisco J. ^{[4
]}

Love, Paul E. ^{[5
]}

Lacy-Hulbert, Adam ^{[5
]}

Blaner, William S. ^{[6
]}

Sparwasser, Tim ^{[7
]}

Snapper, Scott B. ^{[2
,3
]}

Weiner, Howard L. ^{[4
]}

Mora, J. Rodrigo ^{[1
]}

机构：

[1] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA

[2] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA

[3] Childrens Hosp, Gastrointestinal Unit, Boston, MA 02115 USA

[4] Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA

[5] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA

[6] Columbia Univ, Dept Med, New York, NY USA

[7] Ctr Expt & Clin Infect Res, Inst Infect Immunol, Hannover, Germany

来源：

GASTROENTEROLOGY | 2011年 / 141卷 / 06期

基金：

美国国家卫生研究院;

关键词：

Immune Regulation; Autoimmunity; Allergy; Intestine; Peyer's Patch; PLASMACYTOID DENDRITIC CELLS; SMALL-INTESTINE; SUPPRESSION; ABSENCE; IL-10; TH17; DISRUPTION; GENERATION; RESPONSES; RECEPTOR;

D O I：

10.1053/j.gastro.2011.09.015

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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 alpha 4 beta 7 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 beta 7(-/-) mice and also blocked the alpha 4 beta 7 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-10R beta(-/-) mice to examine the role of interleukin (IL)-10 in induction of OT. RESULTS: OT could not be induced in CCR9(-/-) or beta 7(-/-) 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 beta 7(-/-) 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 beta 7(-/-) T cells to wild-type mice partially inhibited OT. CONCLUSIONS: Expression of CCR9 and alpha 4 beta 7 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.

引用

页码：2109 / 2118

页数：10

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