ERK signaling is a molecular switch integrating opposing inputs from B cell receptor and T cell cytokines to control TLR4-driven plasma cell differentiation

Lixin Rui, James I. Healy, Julie Blasioli, Christopher C. Goodnow*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    69 Citations (Scopus)

    Abstract

    Differentiation of B cells into plasma cells represents a critical immunoregulatory checkpoint where neutralizing Abs against infectious agents mast be selected whereas self-reactive Abs are suppressed. Bacterial LPS is a uniquely potent bacterial immunogen that can bypass self-tolerance within the T cell repertoire. We show here that during LPS-induced plasma cell differentiation, the ERK intracellular signaling pathway serves as a pivotal switch integrating opposing inputs from Ag via BCR and from the two best characterized B cell differentiation factors made by T cells, IL-2 and IL-5. Continuous Ag receptor signaling through the RAS/MEK/ERK pathway, as occurs in self-reactive B cells, inhibits LPS induction of Blimp-1 and the plasma cell differentiation program. Differentiation resumes after a transient pulse of Ag-ERK signaling, or upon inactivation of ERK by IL-2 and IL-5 through induction of dual-specificity phosphatase 5 (Dusp5). The architecture of this molecular switch provides a framework for understanding the specificity of antibacterial Ab responses and resistance to bacterially induced autoimmune diseases such as Guillain-Barré syndrome.

    Original languageEnglish
    Pages (from-to)5337-5346
    Number of pages10
    JournalJournal of Immunology
    Volume177
    Issue number8
    DOIs
    Publication statusPublished - 15 Oct 2006

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