Of a distant T-bet enhancer responsive to IL-12/Stat4 and IFNγ/Stat1 signals

被引：65

作者：

Yang, Yu

Ochando, Jordi C.

Bromberg, Jonathan S.

Ding, Yaozhong

机构：

[1] Mt Sinai Sch Med, Dept Gene & Cell Med, New York, NY 10029 USA

[2] Mt Sinai Sch Med, Dept Surg, New York, NY 10029 USA

[3] Mt Sinai Sch Med, Ctr Immunobiol, New York, NY 10029 USA

[4] Mt Sinai Sch Med, Recanati Miller Transplant Inst, New York, NY 10029 USA

来源：

BLOOD | 2007年 / 110卷 / 07期

关键词：

IFN-GAMMA PRODUCTION; TRANSCRIPTION FACTOR; DNA-BINDING; LINEAGE COMMITMENT; INTERFERON-GAMMA; CELL-ACTIVATION; CUTTING EDGE; TH2; CELLS; EXPRESSION; DIFFERENTIATION;

D O I：

10.1182/blood-2006-11-058271

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

T-bet plays a critical role in controlling IFN gamma expression, Th1 polarization, and CD8 cytolytic development. Its regulation has been demonstrated to be mostly IFN gamma/Stat1 dependent while IL-12/Stat4 independent. Here we show that IL-12/Stat4 binds to a distant highly conserved STAT-responsive T-bet enhancer, and induces IFN gamma/Stat1-independent T-bet expression in CD8 T cells. Luciferase reporter assay showed that both Stat4 and Stat1 activate reporter gene expression from constructs containing a wild-type but not mutated T-bet enhancer. Studies in virus-infected mice demonstrated that the IL-12/Stat4/T-bet cascade operates in vivo and regulates IFN gamma in CD8 T cells. Together, we provide a novel mechanism for T-bet regulation, and suggest that IL-12/Stat4/T-bet play an important role in CD8 effector responses.

引用

收藏

页码：2494 / 2500

页数：7

相关论文

共 39 条

[1] T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells [J].

Afkarian, M ;

Sedy, JR ;

Yang, J ;

Jacobson, NG ;

Cereb, N ;

Yang, SY ;

Murphy, TL ;

Murphy, KM .

NATURE IMMUNOLOGY, 2002, 3 (06) :549-557

[2] Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis [J].

Bettelli, E ;

Sullivan, B ;

Szabo, SJ ;

Sobel, RA ;

Glimcher, H ;

Kuchroo, VK .

JOURNAL OF EXPERIMENTAL MEDICINE, 2004, 200 (01) :79-87

[3] Differential chemokine and chemokine receptor gene induction by ischemia, alloantigen, and gene transfer in cardiac grafts [J].

Chen, DM ;

Ding, YZ ;

Schröppel, B ;

Zhang, N ;

Fu, S ;

Chen, D ;

Zhang, HJ ;

Bromberg, JS .

AMERICAN JOURNAL OF TRANSPLANTATION, 2003, 3 (10) :1216-1229

[4] Suppressor. of cytokine signaling 1 inhibits IL-10-mediated immune responses [J].

Ding, YZ ;

Chen, DM ;

Tarcsafalvi, A ;

Su, RH ;

Qin, LH ;

Bromberg, JS .

JOURNAL OF IMMUNOLOGY, 2003, 170 (03) :1383-1391

[5] Differential IL-10R1 expression plays a critical role in IL-10-mediated immune regulation [J].

Ding, YZ ;

Qin, LH ;

Zamarin, D ;

Kotenko, SV ;

Pestka, S ;

Moore, KW ;

Bromberg, JS .

JOURNAL OF IMMUNOLOGY, 2001, 167 (12) :6884-6892

[6] DNA binding specificity of different STAT proteins -: Comparison of in vitro specificity with natural target sites [J].

Ehret, GB ;

Reichenbach, P ;

Schindler, U ;

Horvath, CM ;

Fritz, S ;

Nabholz, M ;

Bucher, P .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (09) :6675-6688

[7] Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet [J].

Finotto, S ;

Neurath, MF ;

Glickman, JN ;

Qin, SX ;

Lehr, HA ;

Green, FHY ;

Ackerman, K ;

Haley, K ;

Gatte, PR ;

Szabo, SJ ;

Drazen, JM ;

De Sanctis, GT ;

Glimcher, LH .

SCIENCE, 2002, 295 (5553) :336-338

[8] Mechanism of transforming growth factor β-induced inhibition of T helper type 1 differentiation [J].

Gorelik, L ;

Constant, S ;

Flavell, RA .

JOURNAL OF EXPERIMENTAL MEDICINE, 2002, 195 (11) :1499-1505

[9] A STAT PROTEIN DOMAIN THAT DETERMINES DNA-SEQUENCE RECOGNITION SUGGESTS A NOVEL DNA-BINDING DOMAIN [J].

HORVATH, CM ;

WEN, ZL ;

DARNELL, JE .

GENES & DEVELOPMENT, 1995, 9 (08) :984-994

[10] T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3 [J].

Hwang, ES ;

Szabo, SJ ;

Schwartzberg, PL ;

Glimcher, LH .

SCIENCE, 2005, 307 (5708) :430-433

← 1 2 3 4 →