Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination.
B cells producing high-affinity antibodies are destined to differentiate into memory B cells and plasma cells, but the mechanisms leading to those differentiation pathways are mostly unknown. Here we report that the transcription factor IRF4 is required for the generation of plasma cells. Transgenic mice with conditional deletion of Irf4 in germinal center B cells lacked post-germinal center plasma cells and were unable to differentiate memory B cells into plasma cells. Plasma cell differentiation required IRF4 as well as the transcriptional repressor Blimp-1, which both acted 'upstream' of the transcription factor XBP-1. In addition, IRF4-deficient B cells had impaired expression of activation-induced deaminase and lacked class-switch recombination, suggesting an independent function for IRF4 in this process. These results identify IRF4 as a crucial transcriptional 'switch' in the generation of functionally competent plasma cells.
Klein
Ulf
U
Institute for Cancer Genetics, Department of Pathology and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
Casola
Stefano
S
Cattoretti
Giorgio
G
Shen
Qiong
Q
Lia
Marie
M
Mo
Tongwei
T
Ludwig
Thomas
T
Rajewsky
Klaus
K
Dalla-Favera
Riccardo
R
D000818:Animals; D000917:Antibody Formation / Q000502:physiology*; D000941:Antigens / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation / Q000502:physiology; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000502:physiology; D018858:Germinal Center / Q000166:cytology / Q000276:immunology; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000502:physiology*; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000235:genetics; D007156:Immunologic Memory / Q000502:physiology; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008213:Lymphocyte Activation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018448:Models, Immunological; D009687:Nuclear Proteins / Q000502:physiology; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051560:Proto-Oncogene Proteins c-bcl-6; D000071701:Regulatory Factor X Transcription Factors; D012097:Repressor Proteins / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic; D000071717:X-Box Binding Protein 1; D000099218:Interferon Regulatory Factor-4
D000941:Antigens; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D050835:Interferon Regulatory Factors; D009687:Nuclear Proteins; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051560:Proto-Oncogene Proteins c-bcl-6; D000071701:Regulatory Factor X Transcription Factors; D012097:Repressor Proteins; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D000099218:Interferon Regulatory Factor-4; C490010:Bcl6 protein, mouse; C513258:Prdm1 protein, mouse; C000605544:Xbp1 protein, mouse