IL-17-induced Regulator of G-protein Signaling orchestrates germinal center kinetics in the onset of autoimmunity in BXD2 mice (159.24)

Abstract

Abstract Development of germinal centers (GCs) is a hallmark of BXD2 autoimmunity. We have shown that IL-17+ CD4 cell frequencies are significantly elevated in the spleen of BXD2 mice, leading to the induction of Regulator of G-protein Signaling (RGS) 13 and 16 and decreased sensitivity to CXCL12 and CXCL13. The resulting chemotactic arrest within the GC promotes extensive somatic hypermutation (SHM) mediated by activation-induced cytidine deaminase (AID). Here we explore mechanisms underlying this phenotype using BXD2-Rgs13-/- and BXD2-Rgs16-/- mice. BXD2-Rgs13-/- mice exhibited higher autoantibody titers in early age compared to wild-type (WT) mice though smaller GCs and lower AID levels suggested a lesser extent of SHM and affinity maturation. There was upregulation of IRF4 in B cells of BXD2-Rgs13-/- mice, suggesting these B cells develop into plasma cells more rapidly than WT B cells. At older ages, BXD2-Rgs13-/- mice showed less IgG deposits in the glomeruli, suggesting reduced autoantibody pathogenicity. RGS16 deficiency led to aberrantly localized T cell zones and reduced aggregation of a population of CD86hi marginal zone precursor (MZP) B cells, accompanied by significantly fewer GCs, suggesting a role in localization of MZP in GC light-zone and B-T co-stimulation events. Taken together, these results suggest a unique role for IL-17 in inducing pathogenic GCs and development of autoimmune disease in BXD2 mice through RGS13 and RGS16-dependent pathways.