The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection

被引：203

作者：

Dominguez, Claudia X. ^{[1
]}

Amezquita, Robert A. ^{[1
,4
]}

Guan, Tianxia ^{[1
]}

Marshall, Heather D. ^{[1
]}

Joshi, Nikhil S. ^{[1
]}

Kleinstein, Steven H. ^{[1
,2
,3
]}

Kaech, Susan M. ^{[1
,4
]}

机构：

[1] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06520 USA

[2] Yale Univ, Sch Med, Interdept Program Computat Biol & Bioinformat, New Haven, CT 06520 USA

[3] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA

[4] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2015年 / 212卷 / 12期

基金：

美国国家卫生研究院;

关键词：

SELECTIVE EXPRESSION; PROTECTIVE IMMUNITY; CUTTING EDGE; MEMORY; EFFECTOR; GENE; GENERATION; SIP1; RECEPTOR; PATHWAY;

D O I：

10.1084/jem.20150186

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

The transcription factor T-bet is critical for cytotoxic T lymphocyte (CTL) differentiation, but it is unclear how it operates in a graded manner in the formation of both terminal effector and memory precursor cells during viral infection. We find that, at high concentrations, T-bet induced expression of Zeb2 mRNA, which then triggered CTLs to adopt terminally differentiated states. ZEB2 and T-bet cooperate to switch on a terminal CTL differentiation program, while simultaneously repressing genes necessary for central memory CTL development. Chromatin immunoprecipitation sequencing showed that a large proportion of these genes were bound by T-bet, and this binding was altered by ZEB2 deficiency. Furthermore, T-bet overexpression could not fully bypass ZEB2 function. Thus, the coordinated actions of T-bet and ZEB2 outline a novel genetic pathway that forces commitment of CTLs to terminal differentiation, thereby restricting their memory cell potential.

引用

页码：2041 / 2056

页数：16

共 61 条

[1] Immunological memory and protective immunity: Understanding their relation [J].