ERK signaling is a molecular switch integrating opposing inputs from B cell receptor and T cell cytokines to control TLR4-driven plasma cell differentiation.
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.
Rui
Lixin
L
Australian Cancer Research Foundation Genetics Laboratory and Medical Genome Centre, John Curtin School of Medical Research, Australian Phenomics Facility, Australian National University, Canberra, Australia.
Healy
James I
JI
Blasioli
Julie
J
Goodnow
Christopher C
CC
D000818:Animals; D000918:Antibody Specificity; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D001419:Bacteria / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D016207:Cytokines / Q000502:physiology*; D054637:Dual-Specificity Phosphatases; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism*; D019409:Interleukin-15 / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D010950:Plasma Cells / Q000166:cytology*; D017027:Protein Tyrosine Phosphatases / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*
D016207:Cytokines; D019409:Interleukin-15; D007376:Interleukin-2; D008070:Lipopolysaccharides; D011947:Receptors, Antigen, B-Cell; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D048049:Extracellular Signal-Regulated MAP Kinases; C442320:DUSP5 protein, human; D054637:Dual-Specificity Phosphatases; D017027:Protein Tyrosine Phosphatases