A contribution of FcγRIIIa cosignaling in TFH subset development in Systemic Lupus Erythematosus

Background: Expansion of follicular helper T cells (T FH ) population occurs in systemic lupus erythematosus (SLE) and their numbers correlate with autoantibody titers. In this study, we sought to examine the role of ICs (FcγRIIIa costimulation) play in T FH cells development. Methods: We examined the presence of blood T FH cells using multicolor flow analysis in SLE patients in vivo. We then examined the development of these cells in vitro using plate-bound ICs. Performed differential expression analysis in cells activated via FcγRIIIa and compared to CD28 cosignaling. Results: In SLE patients PBMCs, CD4+ gated T cells show IC binding and phosphorylated spleen tyrosine kinase (pSyk). These pSyk+ cells express PD1, ICOS, IL-21, and Bcl6, the T FH population markers. In vitro activation from plate-bound ICs of human CD4+ T cells results in the differentiation of T FH like cells phenotype. We show that FcγRIIIa-pSyk cosignaling in Bcl6+IL-21+ cells drives the production of both IFN-γ (T FH 1) and IL-17A (T FH 17) production. TLR9 engagement by CpG ODN 2006 combined with FcγRIIIa costimulation of CD4+ T cells augments, IL-17A, IL-21 production in Bcl6+ T cells. FcγRIIIa cosignaling induced the overexpression of microRNAs that participate in TLR signaling and are associated with TFH cell differentiation. RNA-seq data reveal pathways that may contribute to the development of T FH cells and nucleic acid sensing. Conclusion: Our results suggest a role for FcγRIIIa receptors in T FH development and a role for nucleic acid sensing in the expansion of T FH cells.