Induction of germ-line γ1 and ε Ig gene expression in murine B cells: IL-4 and the CD40 ligand-CD40 interaction provide distinct but synergistic signals

W. D. Warren, M. T. Berton

Research output: Contribution to journalArticle

103 Scopus citations

Abstract

The interaction between B cell CD40 and its ligand (CD40L) on activated Th cells provides a critical signal necessary for T cell-dependent isotype switching. Previous studies suggest that this signal might be important in regulating isotype switching at the level of germ-line Ig transcription. To assess the effects of the CD40L-CD40 interaction on germline Ig transcript expression in murine B cells, a membrane-bound form of mouse CD40L was expressed in the baculovirus system. We show that stimulation of resting splenic B cells with CD40L-expressing Sf9 cells induces germ-line γ1 and ε transcripts independently of cytokines. The CD40-mediated induction cannot be blocked by anti-IL-4 Ab and is not mediated by other cytokines secreted endogenously in response to CD40 stimulation. Importantly, stimulation with CD40L and IL-4 together has a significant synergistic effect on germ-line transcript expression. Stimulation of CD40 does not activate the NF-IL-4-γ1 DNA binding factor believed to be required for IL-4-dependent germ-line γ1 transcription. Moreover, mutation of the NF-IL-4-γ1 DNA binding site in a germ-line γ1 promoter-luciferase reporter gene construct completely ablates IL-4 responsiveness but has no effect on responsiveness to CD40L in transient transfection assays. These results demonstrate that the CD40L-CD40 interaction and IL-4 activate germ-line Ig gene transcription by distinct but synergistic mechanisms and suggest that multiple signals may be required to induce sufficient germ-line transcription and/or germ-line transcript levels necessary to target switch recombination.

Original languageEnglish (US)
Pages (from-to)5637-5646
Number of pages10
JournalJournal of Immunology
Volume155
Issue number12
StatePublished - Jan 1 1995

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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