The artificial loss of Runx1 reduces the expression of quiescence-associated transcription factors in CD4(+) T lymphocytes.
The Runx1 transcription factor cooperates with or antagonizes other transcription factors and plays essential roles in the differentiation and function of T lymphocytes. Previous works showed that Runx1 is expressed in peripheral CD4(+) T cells which level declines after T cell receptor (TCR) activation, and artificial deletion of Runx1 causes autoimmune lung disease in mice. The present study addresses the mechanisms by which Runx1 contributes to the maintenance of peripheral CD4(+) T cell quiescence. Microarray and quantitative RT-PCR analyses were employed to compare the transcriptome of Runx1 -/- CD4(+) T cells to those of unstimulated and TCR-stimulated Runx1 +/- cells. The results identified genes whose expression was modulated similarly by Runx1 deletion and TCR activation. Among them, genes encoding cytokines, chemokines, and Jak/STAT signaling molecules were substantially induced. In Runx1-deleted T cells, simultaneous increases in Il-17A and Rorγc, a known master gene in TH17 differentiation, were observed. In addition, we observed that the loss of Runx1 reduced the transcription of genes encoding quiescence-associated transcription factors, including Foxp1, Foxo1, and Klf2. Interestingly, we identified consensus Runx1 binding sites at the promoter regions of Foxp1, Foxo1, and Klf2 genes, which can be enriched by chromatin immunoprecipitation assay with an anti-Runx1 antibody. Therefore, we suggest that Runx1 may activate, directly or indirectly, the expression of quiescence-associated molecules and thereby contribute to the maintenance of quiescence in CD4(+) T cells.
Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; Department of Molecular Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan. Electronic address: wonfen@um.edu.my.
Won Fen
WF
Wong
Department of Molecular Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan; Cancer Science Institute, National University of Singapore, Singapore 117599, Singapore.
Kazuyoshi
K
Kohu
Division of Cell Proliferation, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Takeshi
T
Nagashima
Division of Cell Proliferation, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Ryo
R
Funayama
Division of Biochemistry, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Mitsuyo
M
Matsumoto
Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Elaheh
E
Movahed
Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Grace Min Yi
GM
Tan
Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Tee Cian
TC
Yeow
Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Chung Yeng
CY
Looi
Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Mineo
M
Kurokawa
Cancer Science Institute, National University of Singapore, Singapore 117599, Singapore.
Motomi
M
Osato
Division of Biochemistry, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Kazuhiko
K
Igarashi
Division of Cell Proliferation, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Keiko
K
Nakayama
Department of Molecular Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Masanobu
M
Satake
D000818:Animals; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D050676:Core Binding Factor Alpha 2 Subunit / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D053612:Janus Kinases / Q000235:genetics / Q000276:immunology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D061166:Peripheral Tolerance / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology*; D050791:STAT Transcription Factors / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000276:immunology
D050676:Core Binding Factor Alpha 2 Subunit; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C432917:Foxp1 protein, mouse; D020381:Interleukin-17; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D012097:Repressor Proteins; C493726:Runx1 protein, mouse; D050791:STAT Transcription Factors; D053612:Janus Kinases
Activated T cells; Cell quiescence; Foxo1; Foxp1; Klf2; Runx1; Transcription factor; microarray