IRF4 Is a Critical Gene in Retinoic Acid-Mediated Plasma Cell Formation and Is Deregulated in Common Variable Immunodeficiency-Derived B Cells.
In the present study, we aimed at identifying the mechanisms whereby the vitamin A metabolite all-trans retinoic acid (RA) promotes the formation of plasma cells upon stimulation of B cells via the innate immunity receptors TLR9 and RP105. Most often, differentiation of B cells involves the sequential events of class switch recombination and somatic hypermutations characteristic of germinal center reactions, followed by plasma cell formation. By studying the regulatory networks known to drive these reactions, we revealed that RA enhances the expression of the plasma cell-generating transcription factors IFN regulatory factor (IRF)4 and Blimp1, and paradoxically also activation-induced deaminase (AID) involved in somatic hypermutations/class switch recombination, in primary human B cells. IRF4 was identified as a particularly important protein involved in the RA-mediated production of IgG in TLR9/RP105-stimulated B cells. Based on kinetic studies, we present a model suggesting that the initial induction of IRF4 by RA favors AID expression. According to this model, the higher level of IRF4 that eventually arises results in sustained elevated levels of Blimp1. Regarded as a master regulator of plasma cell development, Blimp1 will in turn suppress AID expression and drive the formation of IgG-secreting plasma cells. Notably, we demonstrated IRF4 to be deregulated in B cells from common variable immunodeficiency patients, contributing to the observed aberrant expression of AID in these patients. Taken together, the present study both provides new insight into the mechanisms whereby RA induces differentiation of B cells and identifies IRF4 as a key to understand the defective functions of B cells in common variable immunodeficiency patients.
Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway;
Randi L
RL
Indrevær
Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway;
Jan Ø
JØ
Moskaug
Department of Nutrition, University of Oslo, N-0317 Oslo, Norway;
Ingvild
I
Paur
Department of Nutrition, University of Oslo, N-0317 Oslo, Norway;
Siv K
SK
Bøhn
Research Institute of Internal Medicine, Oslo University Hospital, University of Oslo, N-0424 Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, University of Oslo, N-0424 Oslo, Norway; and.
Silje F
SF
Jørgensen
Department of Nutrition, University of Oslo, N-0317 Oslo, Norway; Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, N-0424 Oslo, Norway.
Rune
R
Blomhoff
Research Institute of Internal Medicine, Oslo University Hospital, University of Oslo, N-0424 Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, University of Oslo, N-0424 Oslo, Norway; and.
Pål
P
Aukrust
Research Institute of Internal Medicine, Oslo University Hospital, University of Oslo, N-0424 Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, University of Oslo, N-0424 Oslo, Norway; and.
Børre
B
Fevang
Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway; h.k.blomhoff@medisin.uio.no.
Heidi K
HK
Blomhoff
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D001483:Base Sequence; D002454:Cell Differentiation / Q000276:immunology; D017074:Common Variable Immunodeficiency / Q000235:genetics / Q000276:immunology*; D003564:Cytidine Deaminase / Q000096:biosynthesis; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D018858:Germinal Center / Q000166:cytology / Q000276:immunology; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D050835:Interferon Regulatory Factors / Q000096:biosynthesis / Q000235:genetics*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010950:Plasma Cells / Q000166:cytology* / Q000276:immunology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D034622:RNA Interference; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology; D014212:Tretinoin / Q000494:pharmacology*; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D000099218:Interferon Regulatory Factor-4
D015703:Antigens, CD; D003564:Cytidine Deaminase; D007074:Immunoglobulin G; D050835:Interferon Regulatory Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D051217:Toll-Like Receptor 9; D014212:Tretinoin; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D000099218:Interferon Regulatory Factor-4; C092722:CD180 protein, human; C495371:TLR9 protein, human; C087042:PRDM1 protein, human