Expansion of T follicular regulatory cells by OX40L-JAG1 co-signaling ameliorates experimental lupus nephritis

Abstract

Abstract Antinuclear autoantibodies (Nabs) promote tissue inflammation involving multiple organs including the kidneys in Systemic Lupus Erythmatosus (SLE). T-follicular helper (TFH) cell-dependent B-cell response plays an essential role in lupus nephritis (LN). TFH and B-cells receive mutual help in the germinal centers (GCs) to enable high-affinity autoantibody production. T follicular regulatory cells (TFR) cells, a specialized subset of CD4+Foxp3+Tregs, suppress GC formation and TFH-dependent B-cell response. Previously, we have shown that the expansion of functional Tregs using soluble OX40L and JAG1 proteins suppressed experimental autoimmune diabetes and thyroiditis. However, unlike other autoimmune diseases, the role of Tregs in lupus remains unresolved. Here, we show that NZBWF1/j mice with severe proteinuria and higher anti-dsDNA IgG levels had increased GC-TFH, GC-B cells, and GC-TFH/GC-TFR ratio in their renal lymph nodes compared to mice with no proteinuria. While total Tregs were significantly higher in mice with proteinuria, GC-TFRs were significantly reduced. Intriguingly, OX40L-JAG1 treatment significantly increased Tregs, GC-TFRs, and reduced GC-TFH/GC-TFR ratio. Periodic OX40L-JAG1 treatment resulted in a significant reduction in GC-B-cells, anti-dsDNA IgG level, proteinuria and kidney pathology, and increased survival. Mechanistic studies showed increased PD1 expression in Tconv cells, Tregs, TFH, and TFR cells, and PD-L1 expression in GC-B-cells suggesting a key role for PD1 signaling in the observed protective effect. Our results show that OX40L-JAG1 treatment expanded TFRs which inhibited GC-B cell activation and NAb production, proteinuria and LN.