#1843 Deletion of IL17-producing follicular helper T cells restrains the germinal center reaction in systemic lupus erythematosus

Background and Aims Systemic lupus erythematosus (SLE) is an autoimmune disorder in which autoantibody formation can lead to severe kidney pathology. Interleukin (IL)17-producing T cells have been suggested to play an important role in the pathogenesis of SLE, and IL-17 inhibition was shown to ameliorate SLE pathology in lupus-prone mice. Moreover, the frequency of circulating follicular helper T (Tfh) cells, a T cell subset that orchestrates the maturation of high-affinity antibodies in the germinal center of secondary lymphoid organs, is associated with disease activity in SLE. Increased frequencies of IL17-producing Tfh have been reported in SLE patients compared to controls, but their role in SLE pathogenesis is still unknown. Method By leveraging the B6.Sle1NZM2410/AegYaa strain, we generated lupus-prone mice in which IL17-producing Tfh cells could be either fate-mapped (SLE Tfh17-FM, Il17aCRERosaLoxSTOPLox-YFPSle1+/+Yaa+) or fate-mapped and selectively depleted by intraperitoneal diphtheria toxin (DT) administration (SLE Tfh17-DTR, Il17aCRERosaLoxSTOPLox-YFPCxcr5LoxSTOPLox-DTRSle1+/+Yaa+). Tfh17-FM and Tfh17-DTR mice (both Sle1−/−Yaa−) were used as controls. Results Tfh17 comprised approximately 0.4% of total splenic Tfh in SLE mice at 6 weeks of life, and DT administration caused potent and selective depletion of these cells in the SLE Tfh17-DTR strain (Fig. 1A). Early Tfh17 deletion from week 4 to week 9 did not modify the increased Tfh frequency observed at 20 weeks in SLE mice, but resulted in long-term reduction of splenic germinal center (GC) B cells and plasmacells (Fig. 1B-C). IL17 receptor A was overexpressed in non-GC B cells and plasmacells of SLE mice compared to controls, suggesting a possible increased susceptibility of these subsets to IL17 (Fig. 1D). SLE Tfh17-DTR mice treated with DT displayed a trend towards decreased anti-DNA levels compared to SLE Tfh17-FM (Fig. 1E), but both glomerular immunocomplex deposition and renal pathology were not significantly impacted (Fig. 1F-G). Conclusion The germinal center reaction is affected by selective depletion of IL17-producing Tfh cells in SLE mice, with reduced differentiation of GC B cells and plasmacells. The modest effect of Tfh17 depletion on autoantibody levels and lupus nephritis pathology suggests that other Tfh subsets may play a role in GC-derived autoantibody generation. In addition, extrafollicular sources may also contribute to autoantibody production in SLE.