IL-21/IL-21R interaction on both CD4 cells and B cells is required to promote autoimmune parameters in chronic graft versus host disease. (44.10)

Abstract

Abstract IL-21 stimulates B cell proliferation, plasma cell (PC) differentiation and germinal center (GC) expansion and it exerts autocrine effects on T follicular B helper cells (TFH) and Th17 cells while downregulating Treg cells. We assessed the effect of IL-21/IL-21R signaling on B cells independent from the effect on CD4 T helper cells using IL-21R-/- or IL-21R+/+ mice as donor or hosts in the P-into-F1 and Bm12-into-B6 models of chronic Graft Versus Host Disease (cGVHD). cGVHD induced by injection of IL-21R-/- CD4 cells from B6 mice into B6D2F1 hosts was characterized by a significant decrease in the expansion of donor CD4, TFH and Th17 cells and an increase in Treg cells compared to IL-21R +/+ donor cells. Furthermore, the number and size of GC, GC B cells and levels of anti-ssDNA antibody (Ab) were significantly decreased. When cGVHD was induced by injecting Bm12 spleen cells into IL-21R+/+ or IL-21R-/- B6 mice, parameters of cGVHD including B cell activation, number and size of GC, percentage of GC B cells and plasmablasts, IgG anti-dsDNA Ab production were significantly decreased compared to IL-21+/+ hosts. Long-term studies showed decreased severity of lupus-like renal disease in the IL-21R-/- hosts. These results suggest that IL-21/IL-21R interaction enhances autoimmune features in lupus by promoting the expansion of TFH and Th17 cells and the downregulation of Treg cells and by promoting the differentiation of autoreactive B cells into autoAb producing cells.