IL-21/IL-21R interactions on host B cells but not on donor CD4 cells are critical for the development of autoimmune features in chronic graft versus host disease. (93.9)

Abstract

Abstract Studies in murine models of lupus have indicated increased production of IL-21 and attenuation of autoimmune features following IL-21 blockade. IL-21 exerts an autocrine effect on T follicular B helper cells (TFH) cells and also stimulates B cell proliferation, plasma cell (PC) differentiation and germinal center (GC) expansion. To determine whether IL-21 promotes systemic lupus through effects on TFH cells or B 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 cGVHD. CGVHD induced by injection of IL-21R-/- CD4 cells from B6 mice into B6D2F1 hosts was characterized by a decrease in the expansion of donor CD4, TFH and GC cells. However, other parameters of cGVHD such as host B cell expansion, MHC class II upregulation, PC differentiation and anti-ssDNA autoantibody production did not differ between groups. In contrast, when cGVHD was induced by injecting Bm12 spleen cells into IL-21R-/- B6 mice, parameters of cGVHD were markedly attenuated compared to IL-21R+/+ hosts. Specifically, MHC class II upregulation of B cells decreased by 32%, PC differentiation by 66%, GC cells by 60% and anti-ssDNA antibody level by 81%. These results suggest that IL-21R signaling on host B cells and possibly myeloid cells but not on Ag-specific CD4 T cells is critical for the initiation and progression of systemic autoimmunity in cGVHD.