Follicular helper T cells are required for systemic autoimmunity

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作者：

MA Linterman，RJ Rigby，RK Wong，D Yu，R Brink，JL Cannons，PL Schwartzberg，MC Cook，GD Walters，CG Vinuesa

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摘要：

Production of high-affinity pathogenic autoantibodies appears to be central to the pathogenesis of lupus. Because normal high-affinity antibodies arise from germinal centers (GCs), aberrant selection of GC B cells, caused by either failure of negative selection or enhanced positive selection by follicular helper T (TFH) cells, is a plausible explanation for these autoantibodies. Mice homozygous for thesanallele ofRoquin,which encodes a RING-type ubiquitin ligase, develop GCs in the absence of foreign antigen, excessive TFHcell numbers, and features of lupus. We postulated a positive selection defect in GCs to account for autoantibodies. We first demonstrate that autoimmunity inRoquinsan/san(sanroque) mice is GC dependent: deletion of one allele ofBcl6specifically reduces the number of GC cells, ameliorating pathology. We show that Roquinsanacts autonomously to cause accumulation of TFHcells. Introduction of a null allele of the signaling lymphocyte activation molecule family adaptorSapinto thesanroquebackground resulted in a substantial and selective reduction insanroqueTFHcells, and abrogated formation of GCs, autoantibody formation, and renal pathology. In contrast, adoptive transfer ofsanroqueTFHcells led to spontaneous GC formation. These findings identify TFHdysfunction within GCs and aberrant positive selection as a pathway to systemic autoimmunity.

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关键词：

Animals Antigens CD28 Antigens Differentiation T-Lymphocyte Autoantibodies 动物抗原 CD28