Control of TH17/Treg Balance by Hypoxia-Inducible Factor 1

被引：1325

作者：

Dang, Eric V. ^{[1
]}

Barbi, Joseph ^{[1
]}

Yang, Huang-Yu ^{[1
,12
]}

Jinasena, Dilini ^{[1
]}

Yu, Hong ^{[1
]}

Zheng, Ying ^{[1
]}

Bordman, Zachary ^{[1
]}

Fu, Juan ^{[2
]}

Kim, Young ^{[2
]}

Yen, Hung-Rong ^{[1
,13
]}

Luo, Weibo ^{[3
,4
,5
,6
,7
,8
]}

Zeller, Karen ^{[9
]}

Shimoda, Larissa ^{[10
]}

Topalian, Suzanne L. ^{[11
]}

Semenza, Gregg L. ^{[3
,4
,5
,6
,7
,8
]}

Dang, Chi V. ^{[9
]}

Pardoll, Drew M. ^{[1
]}

Pan, Fan ^{[1
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Immunol & Hematopoiesis Div, Dept Oncol & Med,Sidney Kimmel Comprehens Canc Ct, Baltimore, MD 21231 USA

[2] Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21231 USA

[3] Johns Hopkins Univ, Sch Med, Vasc Program, Inst Cell Engn,Dept Pediat, Baltimore, MD 21231 USA

[4] Johns Hopkins Univ, Sch Med, Vasc Program, Inst Cell Engn,Dept Med, Baltimore, MD 21231 USA

[5] Johns Hopkins Univ, Sch Med, Vasc Program, Inst Cell Engn,Dept Oncol, Baltimore, MD 21231 USA

[6] Johns Hopkins Univ, Sch Med, Vasc Program, Inst Cell Engn,Dept Radiat Oncol, Baltimore, MD 21231 USA

[7] Johns Hopkins Univ, Sch Med, Vasc Program, Inst Cell Engn,Dept Biol Chem, Baltimore, MD 21231 USA

[8] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21231 USA

[9] Johns Hopkins Univ, Sch Med, Div Hematol, Dept Med, Baltimore, MD 21231 USA

[10] Johns Hopkins Univ, Sch Med, Div Pulm & Crit Care Med, Dept Med, Baltimore, MD 21231 USA

[11] Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21231 USA

[12] Chang Gung Univ, Coll Med, Dept Nephrol, Chang Gung Mem Hosp, Tao Yuan 333, Taiwan

[13] Chang Gung Univ, Coll Med, Dept Pediat, Chang Gung Mem Hosp,Ctr Tradit Chinese Med, Tao Yuan 333, Taiwan

来源：

CELL | 2011年 / 146卷 / 05期

关键词：

REGULATORY T-CELLS; TGF-BETA; CUTTING EDGE; DIFFERENTIATION; EFFECTOR; ACTIVATION; TH17; INDUCTION; MTOR; AUTOIMMUNITY;

D O I：

10.1016/j.cell.2011.07.033

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

T cell differentiation into distinct functional effector and inhibitory subsets is regulated, in part, by the cytokine environment present at the time of antigen recognition. Here, we show that hypoxia-inducible factor 1 (HIF-1), a key metabolic sensor, regulates the balance between regulatory T cell (T-reg) and T(H)17 differentiation. HIF-1 enhances T(H)17 development through direct transcriptional activation of ROR gamma t and via tertiary complex formation with ROR gamma t and p300 recruitment to the IL-17 promoter, thereby regulating T(H)17 signature genes. Concurrently, HIF-1 attenuates T-reg development by binding Foxp3 and targeting it for proteasomal degradation. Importantly, this regulation occurs under both normoxic and hypoxic conditions. Mice with HIF-1 alpha-deficient T cells are resistant to induction of T(H)17-dependent experimental autoimmune encephalitis associated with diminished T(H)17 and increased T-reg cells. These findings highlight the importance of metabolic cues in T cell fate determination and suggest that metabolic modulation could ameliorate certain T cell-based immune pathologies.

引用

页码：772 / 784

页数：13

共 48 条

[11] TH 17 cells in development:: an updated view of their molecular identity and genetic programming [J].