Tcf1 and Lef1 transcription factors establish CD8(+) T cell identity through intrinsic HDAC activity.
The CD4(+) and CD8(+) T cell dichotomy is essential for effective cellular immunity. How individual T cell identity is established remains poorly understood. Here we show that the high-mobility group (HMG) transcription factors Tcf1 and Lef1 are essential for repressing CD4(+) lineage-associated genes including Cd4, Foxp3 and Rorc in CD8(+) T cells. Tcf1- and Lef1-deficient CD8(+) T cells exhibit histone hyperacetylation, which can be ascribed to intrinsic histone deacetylase (HDAC) activity in Tcf1 and Lef1. Mutation of five conserved amino acids in the Tcf1 HDAC domain diminishes HDAC activity and the ability to suppress CD4(+) lineage genes in CD8(+) T cells. These findings reveal that sequence-specific transcription factors can utilize intrinsic HDAC activity to guard cell identity by repressing lineage-inappropriate genes.
Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
Shaojun
S
Xing
Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
Fengyin
F
Li
Department of Physics, The George Washington University, Washington, DC, USA.
Zhouhao
Z
Zeng
Department of Physics, The George Washington University, Washington, DC, USA.
Yunjie
Y
Zhao
State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
Shuyang
S
Yu
Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
Qiang
Q
Shan
Proteomics Facility, University of Iowa, Iowa City, Iowa, USA.
Yalan
Y
Li
Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.|Interdisciplinary Immunology Graduate Program, University of Iowa, Iowa City, Iowa, USA.
Farrah C
FC
Phillips
Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
Peterson K
PK
Maina
Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
Hank H
HH
Qi
Transgenic Core Facility, NHLBI, National Institutes of Health, Bethesda, Maryland, USA.
Chengyu
C
Liu
Systems Biology Center, NHLBI, National Institutes of Health, Bethesda, Maryland, USA.
Jun
0000-0003-4573-8933
J
Zhu
Proteomics Facility, University of Iowa, Iowa City, Iowa, USA.
R Marshall
RM
Pope
Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
Catherine A
CA
Musselman
Department of Physics, The George Washington University, Washington, DC, USA.
Chen
C
Zeng
Department of Physics, The George Washington University, Washington, DC, USA.
Weiqun
W
Peng
Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.|Interdisciplinary Immunology Graduate Program, University of Iowa, Iowa City, Iowa, USA.
Hai-Hui
HH
Xue
D000107:Acetylation; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D000072417:Protein Domains / Q000235:genetics
D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D006655:Histone Deacetylases