title: Fine tuning of IRF-4 expression by SWAP-70 controls the initiation of plasma cell development.
abstract: The generation of plasma cells (PCs) is key for proper humoral immune responses. The transcription factors IRF-4 and BLIMP-1 (B-lymphocyte induce maturation protein-1) control PC commitment, but the underlying regulatory mechanisms are incompletely understood. Here we have identified SWAP-70 as being critically involved in Toll-like receptor (TLR)-triggered PC differentiation. Upon activation through various TLRs, Swap-70(-/-)  B cells were activated and proliferated normally. However, expression of BLIMP-1 was markedly reduced and PC differentiation was impaired. Four hours of LPS stimulation were sufficient to drive PC differentiation, and SWAP-70 was required during this initial period. Swap-70(-/-)  B cells pre-activated in vitro failed to efficiently differentiate into PCs upon adoptive transfer into recipient mice. Re-introduction of SWAP-70 into Swap-70(-/-)  B cells rescued their development into PCs, and SWAP-70 over-expression in wild-type (WT) B cells increased PC generation. In the absence of SWAP-70, IRF-4 protein levels were reduced and the IRF-4(high)  B220(+)  CD138(-)  compartment, including PC precursors, was strongly diminished. Ectopic expression of SWAP-70 increases IRF-4 protein levels and PC differentiation in WT and Swap-70(-/-)  B cells, and IRF-4 over-expression in Swap-70(-/-)  B cells elevates PC differentiation to WT levels. Thus, in a dose-dependent manner, SWAP-70 controls IRF-4 protein expression and thereby regulates the initiation of PC differentiation.
authors: Institute of Physiological Chemistry, Faculty of Medicine Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.
authors: Michaël
authors: M
authors: Chopin
authors: Carlos Andrés
authors: CA
authors: Chacón-Martínez
authors: Rolf
authors: R
authors: Jessberger
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D001402:B-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D056724:Immunity, Humoral; D015151:Immunoblotting; D050835:Interferon Regulatory Factors / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins / Q000378:metabolism*; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*; D000099218:Interferon Regulatory Factor-4
chemical_list: D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D050835:Interferon Regulatory Factors; D008070:Lipopolysaccharides; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051193:Toll-Like Receptors; D014157:Transcription Factors; D000099218:Interferon Regulatory Factor-4; C513258:Prdm1 protein, mouse; C113365:Swap70 protein, mouse