Fine tuning of IRF-4 expression by SWAP-70 controls the initiation of plasma cell development

Eur J Immunol. 2011 Oct;41(10):3063-74. doi: 10.1002/eji.201141742. Epub 2011 Aug 30.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal
  • B-Lymphocytes / metabolism
  • Cell Differentiation*
  • DNA-Binding Proteins / metabolism*
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Immunity, Humoral
  • Immunoblotting
  • Interferon Regulatory Factors / biosynthesis*
  • Lipopolysaccharides / pharmacology
  • Lymphocyte Activation
  • Mice
  • Mice, Knockout
  • Minor Histocompatibility Antigens
  • Nuclear Proteins / metabolism*
  • Plasma Cells / cytology
  • Plasma Cells / immunology
  • Plasma Cells / metabolism*
  • Polymerase Chain Reaction
  • Positive Regulatory Domain I-Binding Factor 1
  • Toll-Like Receptors / immunology
  • Toll-Like Receptors / metabolism
  • Transcription Factors / biosynthesis
  • Transcription Factors / metabolism*

Substances

  • Antibodies, Monoclonal
  • DNA-Binding Proteins
  • Guanine Nucleotide Exchange Factors
  • Interferon Regulatory Factors
  • Lipopolysaccharides
  • Minor Histocompatibility Antigens
  • Nuclear Proteins
  • Prdm1 protein, mouse
  • Swap70 protein, mouse
  • Toll-Like Receptors
  • Transcription Factors
  • interferon regulatory factor-4
  • Positive Regulatory Domain I-Binding Factor 1