ERK signaling is a molecular switch integrating opposing inputs from B cell receptor and T cell cytokines to control TLR4-driven plasma cell differentiation.
Autor(es): Rui Lixin; Healy James I.; Blasioli Julie; Goodnow Christopher C.
Resumo: Differentiation of B cells into plasma cells represents a critical immunoregulatory checkpoint where neutralizing Abs against infectious agents must 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.
Imprenta: Journal of Immunology, v. 177, n. 8, p. 5337-5346, 2006
Identificador do objeto digital: 10.4049/jimmunol.177.8.5337
Descritores: Guillain-Barre Syndrome - Biosynthesis ; Guillain-Barre Syndrome - Cell ; Guillain-Barre Syndrome - Genome ; Guillain-Barre Syndrome - Pathogenesis ; Guillain-Barre Syndrome - Proteins ; Guillain-Barre Syndrome - Cytokines ; Guillain-Barre Syndrome - Infectious diseases ; Guillain-Barre Syndrome - Immunology
Data de publicação: 2006