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

共 45 条

[11] Sequential Role of Plasmacytoid Dendritic Cells and Regulatory T Cells in Oral Tolerance [J].

Dubois, Bertrand ;

Joubert, Gregoire ;

de Agueero, Mercedes Gomez ;

Gouanvic, Marie ;

Goubier, Anne ;

Kaiserlian, Dominique .

GASTROENTEROLOGY, 2009, 137 (03) :1019-1028

[12] Lymphocyte homing and its role in the pathogenesis of IBD [J].

Eksteen, Bertus ;

Liaskou, Evaggelia ;

Adams, David H. .

INFLAMMATORY BOWEL DISEASES, 2008, 14 (09) :1298-1312

[13] CCL25/CCR9 promotes the induction and function of CD103 on intestinal intraepithelial lymphocytes [J].

Ericsson, A ;

Svensson, M ;

Arya, A ;

Agace, WW .

EUROPEAN JOURNAL OF IMMUNOLOGY, 2004, 34 (10) :2720-2729

[14] Oral tolerance [J].

Faria, AMC ;

Weiner, HL .

IMMUNOLOGICAL REVIEWS, 2005, 206 :232-259

[15]

FERGUSON A, 1983, ANN ALLERGY, V51, P246

[16] Plasmacytoid dendritic cells mediate oral tolerance [J].

Goubier, Anne ;

Dubois, Bertrand ;

Gheit, Hanane ;

Joubert, Grgoire ;

Villard-Truc, Florence ;

Asselin-Paturel, Carine ;

Trinchieri, Giorgio ;

Kaiserlian, Dominique .

IMMUNITY, 2008, 29 (03) :464-475

[17] CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease [J].

Hadeiba, Husein ;

Sato, Tohru ;

Habtezion, Aida ;

Oderup, Cecilia ;

Pan, Junliang ;

Butcher, Eugene C. .

NATURE IMMUNOLOGY, 2008, 9 (11) :1253-1260

[18] Intestinal Tolerance Requires Gut Homing and Expansion of FoxP3+ Regulatory T Cells in the Lamina Propria [J].

Hadis, Usriansyah ;

Wahl, Benjamin ;

Schulz, Olga ;

Hardtke-Wolenski, Matthias ;

Schippers, Angela ;

Wagner, Norbert ;

Mueller, Werner ;

Sparwasser, Tim ;

Foerster, Reinhold ;

Pabst, Oliver .

IMMUNITY, 2011, 34 (02) :237-246

[19] Functional CD25- and CD25+ mucosal regulatory T cells are induced in gut-draining lymphoid tissue within 48 h after oral antigen application [J].

Hauet-Broere, F ;

Unger, WWJ ;

Garssen, J ;

Hoijer, MA ;

Kraal, G ;

Samsom, JN .

EUROPEAN JOURNAL OF IMMUNOLOGY, 2003, 33 (10) :2801-2810

[20] Retinoic acid imprints gut-homing specificity on T cells [J].

Iwata, M ;

Hirakiyama, A ;

Eshima, Y ;

Kagechika, H ;

Kato, C ;

Song, SY .

IMMUNITY, 2004, 21 (04) :527-538

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