The Xenobiotic Transporter Mdr1 Enforces T Cell Homeostasis in the Presence of Intestinal Bile Acids

被引：81

作者：

Cao, Wei ^{[1
]}

Kayama, Hisako ^{[2
]}

Chen, Mei Lan ^{[1
]}

Delmas, Amber ^{[1
]}

Sun, Amy ^{[3
]}

Kim, Sang Yong ^{[4
]}

Rangarajan, Erumbi S. ^{[5
]}

McKevitt, Kelly ^{[1
]}

Beck, Amanda P. ^{[6
,13
]}

Jackson, Cody B. ^{[1
]}

Crynen, Gogce ^{[7
]}

Oikonomopoulos, Angelos ^{[8
]}

Lacey, Precious N. ^{[8
]}

Martinez, Gustavo J. ^{[9
]}

Izard, Tina ^{[5
]}

Lorenz, Robin G. ^{[10
]}

Rodriguez-Palacios, Alex ^{[11
]}

Cominelli, Fabio ^{[11
]}

Abreu, Maria T. ^{[12
]}

Hommes, Daniel W. ^{[8
]}

Koralov, Sergei B. ^{[3
]}

Takeda, Kiyoshi ^{[2
]}

Sundrud, Mark S. ^{[1
]}

机构：

[1] Scripps Res Inst, Dept Immunol & Microbiol, Jupiter, FL 33458 USA

[2] Osaka Univ, Grad Sch Med, Dept Microbiol & Immunol, Osaka 5650871, Japan

[3] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA

[4] NYU, Sch Med, Rodent Genet Engn Core, New York, NY 10016 USA

[5] Scripps Res Inst, Dept Integrat Struct & Computat Biol, Jupiter, FL 33458 USA

[6] MD Anderson Canc Ctr, Dept Vet Sci, Bastrop, TX 78602 USA

[7] Scripps Res Inst, Bioinformat Core Facil, Jupiter, FL 33458 USA

[8] Univ Calif Los Angeles, David Geffen Sch Med, Vatche & Tamar Manoukian Div Digest Dis, Los Angeles, CA 90095 USA

[9] Rosalind Franklin Univ Med & Sci, Chicago Med Sch, Dept Microbiol & Immunol, N Chicago, IL 60064 USA

[10] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA

[11] Case Western Reserve Univ, Sch Med, Digest Hlth Res Inst, Cleveland, OH 44106 USA

[12] Univ Miami, Miller Sch Med, Dept Med, Div Gastroenterol, Miami, FL 33136 USA

[13] Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10461 USA

来源：

IMMUNITY | 2017年 / 47卷 / 06期

基金：

日本科学技术振兴机构;

关键词：

INFLAMMATORY-BOWEL-DISEASE; P-GLYCOPROTEIN; MULTIDRUG-RESISTANCE; MICE; CD4(+); TRAFFICKING; ACTIVATION; MECHANISMS; MICROBIOTA; BACTERIA;

D O I：

10.1016/j.immuni.2017.11.012

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

CD4(+) T cells are tightly regulated by microbiota in the intestine, but whether intestinal T cells interface with host-derived metabolites is less clear. Here, we show that CD4(+) T effector (Teff) cells upregulated the xenobiotic transporter, Mdr1, in the ileum to maintain homeostasis in the presence of bile acids. Whereas wild-type Teff cells upregulated Mdr1 in the ileum, those lacking Mdr1 displayed mucosal dysfunction and induced Crohn's disease-like ileitis following transfer into Rag1(-/-) hosts. Mdr1 mitigated oxidative stress and enforced homeostasis in Teff cells exposed to conjugated bile acids (CBAs), a class of liver-derived emulsifying agents that actively circulate through the ileal mucosa. Blocking ileal CBA reabsorption in transferred Rag1(-/-) mice restored Mdr1-deficient Teff cell homeostasis and attenuated ileitis. Further, a subset of ileal Crohn's disease patients displayed MDR1 loss of function. Together, these results suggest that coordinated interaction between mucosal Teff cells and CBAs in the ileum regulate intestinal immune homeostasis.

引用

页码：1182 / +

页数：24

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