Kruppel-like Factor KLF10 Targets Transforming Growth Factor-β1 to Regulate CD4+CD25- T Cells and T Regulatory Cells

被引:85
作者
Cao, Zhuoxiao [1 ]
Wara, Akm Khyrul [1 ]
Icli, Basak [1 ]
Sun, Xinghui [1 ]
Packard, Rene R. S. [1 ]
Esen, Fehim [1 ]
Stapleton, Christopher J. [1 ,6 ]
Subramaniam, Malayannan [2 ]
Kretschmer, Karsten [3 ]
Apostolou, Irina [3 ]
von Boehmer, Harald [3 ]
Hansson, Goran K. [4 ,5 ]
Spelsberg, Thomas C. [2 ]
Libby, Peter [1 ]
Feinberg, Mark W. [1 ]
机构
[1] Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp,Cardiovasc Div, Boston, MA 02115 USA
[2] Mayo Clin, Dept Biochem & Mol Biol, Coll Med, Rochester, MN 55905 USA
[3] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA
[4] Karolinska Inst, Ctr Mol Med, SE-17176 Stockholm, Sweden
[5] Karolinska Inst, Dept Med, SE-17176 Stockholm, Sweden
[6] Harvard Univ, Sch Med, Harvard Massachusetts Inst Technol, Div Hlth Sci & Technol, Boston, MA 02115 USA
基金
瑞典研究理事会; 美国国家卫生研究院;
关键词
GROWTH-FACTOR-BETA; TRANSCRIPTION FACTOR FOXP3; TGF-BETA; CUTTING EDGE; TRANSPLANT ARTERIOSCLEROSIS; ACCELERATES ATHEROSCLEROSIS; AGGRAVATES ATHEROSCLEROSIS; VASCULAR INFLAMMATION; PERIPHERAL TOLERANCE; FACTOR EKLF;
D O I
10.1074/jbc.M109.000059
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
CD4(+)CD25(+) regulatory T cells (T regs) play a major role in the maintenance of self-tolerance and immune suppression, although the mechanisms controlling T reg development and suppressor function remain incompletely understood. Herein, we provide evidence that Kruppel-like factor 10 (KLF10/TIEG1) constitutes an important regulator of T regulatory cell suppressor function and CD4(+)CD25(-) T cell activation through distinct mechanisms involving transforming growth factor (TGF)-beta 1 and Foxp3. KLF10 overexpressing CD4(+)CD25(-) T cells induced both TGF-beta 1 and Foxp3 expression, an effect associated with reduced T-Bet (Th1 marker) and Gata3 (Th2 marker) mRNA expression. Consistently, KLF10(-/-) CD4(+)CD25(-) T cells have enhanced differentiation along both Th1 and Th2 pathways and elaborate higher levels of Th1 and Th2 cytokines. Furthermore, KLF10(-/-) CD4(+)CD25(-) T cell effectors cannot be appropriately suppressed by wild-type T regs. Surprisingly, KLF10(-/-) T reg cells have reduced suppressor function, independent of Foxp3 expression, with decreased expression and elaboration of TGF-beta 1, an effect completely rescued by exogenous treatment with TGF-beta 1. Mechanistic studies demonstrate that in response to TGF-beta 1, KLF10 can transactivate both TGF-beta 1 and Foxp3 promoters, implicating KLF10 in a positive feedback loop that may promote cell-intrinsic control of T cell activation. Finally, KLF10(-/-) CD4(+)CD25(-) T cells promoted atherosclerosis by similar to 2-fold in ApoE(-/-)/scid/scid mice with increased leukocyte accumulation and peripheral pro-inflammatory cytokines. Thus, KLF10 is a critical regulator in the transcriptional network controlling TGF-beta 1 in both CD4(+)CD25(-) T cells and T regs and plays an important role in regulating atherosclerotic lesion formation in mice.
引用
收藏
页码:24914 / 24924
页数:11
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