Interferon regulatory factor 4 regulates thymocyte differentiation by repressing Runx3 expression.
The transcription factor interferon regulatory factor 4 (IRF4) was originally found to be preferentially expressed in lymphoid cells and to be required for the function, differentiation, and homeostasis of both mature T and B lymphocytes. Recent studies have indicated that IRF4 is also involved in early B-cell development. However, the role of IRF4 in intrathymic T-cell development remains unknown. In this study, we show that IRF4 is upregulated in TCR-signaled thymocytes and is predominantly expressed in CD4 single-positive (SP), but not in CD8 SP, cells. T-cell-specific overexpression of IRF4 impaired the generation and maturation of CD8 SP thymocytes. Further analysis revealed that IRF4 selectively bound to the distal promoter region of Runx3 and repressed its transcription, probably through the deacetylation of histones H3 and H4 in intermediate CD4(+) CD8(low) cells and CD4 SP thymocytes. Similar to the effect of Runx3 deficiency, transgenic expression of IRF4 led not only to an aberrantly high expression of CD4 surface molecules on intermediate CD4(+) CD8(low) cells and CD8 SP thymocytes, but also impaired CD8(+) T-cell function. Taken together, our data suggest that IRF4 plays an important role in the regulation of Runx3 expression and CD4(+) /CD8(+) thymocyte differentiation.
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, P. R. China.
Yonghao
Y
Cao
Hai
H
Li
Yang
Y
Sun
Xufeng
X
Chen
Haifeng
H
Liu
Xiang
X
Gao
Xiaolong
X
Liu
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D006657:Histones / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology; D000099218:Interferon Regulatory Factor-4
D015704:CD4 Antigens; D050677:Core Binding Factor Alpha 3 Subunit; D006657:Histones; D050835:Interferon Regulatory Factors; D000099218:Interferon Regulatory Factor-4; C493730:Runx3 protein, mouse