title: Dual signaling by innate and adaptive immune receptors is required for TLR7-induced B-cell-mediated autoimmunity.
abstract: Toll-like receptor 7 (Tlr7) has been linked to systemic lupus disease incidence in humans and mice, but how TLR7 potentiates autoimmunity is unclear. We used a Tlr7 transgenic (tg) mouse model to investigate the cellular and molecular events required to induce spontaneous autoimmunity through increased TLR7 activity. We determined that Tlr7 exerts B-cell-intrinsic effects in promoting spontaneous germinal center (GC) and plasmablast B-cell development, and that these B-cell subsets are dependent on T-cell-derived signals through CD40L and SLAM-associated protein (SAP), but not IL-17. Antigen specificity also factored into TLR7-induced disease, as both a restricted T cell receptor (TCR) specificity and MHC haplotype H2(k/k) protected Tlr7tg mice from spontaneous lymphocyte activation and autoantibody production. Inflammatory myeloid cell expansion and autoimmunity did not develop in Tlr7tgIgH(-/-) mice, suggesting either that spontaneous TLR7 activation does not occur in dendritic cells, or, if it does occur, cannot drive these events in the absence of B-cell aid. These data indicate that autoimmune disease in Tlr7tg mice is contingent upon B cells receiving stimulation both through innate pathways and T-cell-derived signals and suggest a codependent relationship between B cells and T cells in the development of autoimmunity.
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Walsh
authors.forename: Prapaporn
authors.initials: P
authors.lastname: Pisitkun
authors.forename: Elisaveta
authors.initials: E
authors.lastname: Voynova
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Deane
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Scott
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Caspi
authors.forename: Silvia
authors.initials: S
authors.lastname: Bolland
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000704:Analysis of Variance; D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D023201:CD40 Ligand / Q000378:metabolism; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000276:immunology*; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D051199:Toll-Like Receptor 7 / Q000276:immunology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011948:Receptors, Antigen, T-Cell; C499569:Sh2d1a protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D051199:Toll-Like Receptor 7; D023201:CD40 Ligand