Lack of IL-21R on donor cells attenuates chronic GVHD but promotes humoral autoimmunity in acute GVHD (56.11)

Abstract

Abstract IL-21 enhances CD8 maturation into cytotoxic T lymphocytes (CTL), promotes the differentiation of T follicular helper cells (TFH) cells and Th17 cells, downregulates Tregulatory (Treg) cells and exerts stimulatory activities on B cells, suggesting a complex role for IL-21 in promoting autoimmunity. To assess the role of IL-21/IL-21R interaction on CD4 and CD8 T cells in promoting lupus-like disease we used the parent-into-F1 model of acute and chronic graft versus host disease (GVHD) using IL-21R KO and wild type B6 mice as donors. cGVHD induced with CD8 depleted splenocytes from IL-21R KO mice exhibited an attenuated disease phenotype characterized by significant decrease in the number of donor (d)CD4 and dTFH cells, impaired help for B cells as determined by anti-ssDNA antibody levels and less severe lupus-like glomerulonephritis. However the balance between IL-17 producing dTh17 cells and FoxP3 dTreg cells was not altered. Acute GVHD induced with IL-21R KO splenocytes resulted in an attenuated disease phenotype as indicated by a significant decrease in dCD4 and CD8 engraftment, decreased host B cell elimination (90%±0.3) compared to wt injected mice (57%±6; p=0.03), decreased anti-host CTL activity and increased anti-ssDNA Ab levels. These results suggest that IL-21/IL-21R interaction on T cells promotes lupus-like cGVHD by sustaining TFH cell number yet it downregulates the humoral component in aGVHD by enhancing host B cells elimination by CTL.