Transitional B cells exhibit a B cell receptor-specific nuclear defect in gene transcription

J Immunol. 2009 Mar 1;182(5):2868-78. doi: 10.4049/jimmunol.0802368.

Abstract

The signaling programs that enforce negative selection in early transitional (T1) B cells in response to BCR engagement remain poorly defined. We conducted a comprehensive comparison of BCR signaling in T1 vs follicular mature splenic B cells. T1, in contrast to follicular mature B cells, failed to express key NF-kappaB target genes in response to BCR engagement and exhibited a striking defect in assembly of an active transcriptional complex at the promoter of the survival and proliferative genes A1 and c-Myc. Surprisingly, and contrary to previous models, classical protein kinase C and IkappaB kinase activation, NF-kappaB nuclear translocation and DNA binding were intact in T1 B cells. Furthermore, despite a marked reduction in NFAT1 expression, differential NFAT or AP-1 activation cannot explain this transcriptional defect. Our combined findings demonstrate that T1 B cells are programmed for signal- and stage-specific "nuclear nonresponsiveness" upon encounter with self-Ags.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / immunology
  • B-Lymphocyte Subsets / immunology*
  • B-Lymphocyte Subsets / metabolism*
  • B-Lymphocyte Subsets / pathology
  • Cell Nucleus / genetics*
  • Cell Nucleus / metabolism
  • Cell Nucleus / pathology
  • Cell Survival
  • Cells, Cultured
  • Epitopes, B-Lymphocyte / immunology*
  • Gene Expression Regulation, Developmental / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, Transgenic
  • Minor Histocompatibility Antigens
  • Models, Immunological
  • NFATC Transcription Factors / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Receptors, Antigen, B-Cell / immunology*
  • Receptors, Antigen, B-Cell / metabolism
  • Transcription, Genetic / immunology*

Substances

  • BCL2-related protein A1
  • Epitopes, B-Lymphocyte
  • Minor Histocompatibility Antigens
  • Myc protein, mouse
  • NFATC Transcription Factors
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-myc
  • Receptors, Antigen, B-Cell