Dual signaling by innate and adaptive immune receptors is required for TLR7-induced B-celL-mediated autoimmunity

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 increa...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2012-10, Vol.109 (4), p.16276
Main Authors: Walsh, Elizabeth R, Pisitkun, Prapaporn, Voynova, Elisaveta, Deane, Jonathan A, Scott, Bethany L, Caspi, Rachel R, Bolland, Silvia
Format: Article
Language:English
Subjects:
Immunity (Disease)
Lupus
Lymphocytes
Proteins
Rodents
Transgenic animals
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Summary: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 H2k/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. [PUBLICATION ABSTRACT]
ISSN:0027-8424
1091-6490