Essential role for the transcription factor Bhlhe41 in regulating the development, self-renewal and BCR repertoire of B-1a cells

Nat Immunol. 2017 Apr;18(4):442-455. doi: 10.1038/ni.3694. Epub 2017 Feb 27.


Innate-like B-1a cells provide a first line of defense against pathogens, yet little is known about their transcriptional control. Here we identified an essential role for the transcription factor Bhlhe41, with a lesser contribution by Bhlhe40, in controlling B-1a cell differentiation. Bhlhe41-/-Bhlhe40-/- B-1a cells were present at much lower abundance than were their wild-type counterparts. Mutant B-1a cells exhibited an abnormal cell-surface phenotype and altered B cell receptor (BCR) repertoire exemplified by loss of the phosphatidylcholine-specific VH12Vκ4 BCR. Expression of a pre-rearranged VH12Vκ4 BCR failed to 'rescue' the mutant phenotype and revealed enhanced proliferation accompanied by increased cell death. Bhlhe41 directly repressed the expression of cell-cycle regulators and inhibitors of BCR signaling while enabling pro-survival cytokine signaling. Thus, Bhlhe41 controls the development, BCR repertoire and self-renewal of B-1a cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocyte Subsets / cytology*
  • B-Lymphocyte Subsets / immunology
  • B-Lymphocyte Subsets / metabolism*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Binding Sites
  • Biomarkers
  • Cell Differentiation* / genetics
  • Cell Self Renewal* / genetics
  • Gene Expression Regulation
  • Genes, Immunoglobulin
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Knockout
  • Nucleotide Motifs
  • Organ Specificity / genetics
  • Organ Specificity / immunology
  • Phenotype
  • Position-Specific Scoring Matrices
  • Promoter Regions, Genetic
  • Protein Binding
  • Receptors, Antigen, B-Cell / metabolism*
  • Repressor Proteins / metabolism
  • Signal Transduction


  • Basic Helix-Loop-Helix Transcription Factors
  • Biomarkers
  • Receptors, Antigen, B-Cell
  • Repressor Proteins