title: Dendritic Cells Regulate Extrafollicular Autoreactive B Cells via T Cells Expressing Fas and Fas Ligand.
abstract: The extrafollicular (EF) plasmablast response to self-antigens that contain Toll-like receptor (TLR) ligands is prominent in murine lupus models and some bacterial infections, but the inhibitors and activators involved have not been fully delineated. Here, we used two conventional dendritic cell (cDC) depletion systems to investigate the role of cDCs on a classical TLR-dependent autoreactive EF response elicited in rheumatoid-factor B cells by DNA-containing immune complexes. Contrary to our hypothesis, cDC depletion amplified rather than dampened the EF response in Fas-intact but not Fas-deficient mice. Further, we demonstrated that cDC-dependent regulation requires Fas and Fas ligand (FasL) expression by T cells, but not Fas expression by B cells. Thus, cDCs activate FasL-expressing T cells that regulate Fas-expressing extrafollicular helper T (Tefh) cells. These studies reveal a regulatory role for cDCs in B cell plasmablast responses and provide a mechanistic explanation for the excess autoantibody production observed in Fas deficiency.
authors: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06519, USA.
authors: Michelle L
authors: ML
authors: Ols
authors: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06519, USA.
authors: Jaime L
authors: JL
authors: Cullen
authors: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors: Adriana
authors: A
authors: Turqueti-Neves
authors: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors: Josephine
authors: J
authors: Giles
authors: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. Electronic address: mshlomch@pitt.edu.
authors: Mark J
authors: MJ
authors: Shlomchik
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D002469:Cell Separation; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D058501:Enzyme-Linked Immunospot Assay; D053222:Fas Ligand Protein / Q000276:immunology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology
chemical_list: D001323:Autoantibodies; D053222:Fas Ligand Protein; D019014:fas Receptor