Immunological effects of interleukin-21 (IL-21) on T-, B-, and NK-cells have been reported, but the role of IL-21 in graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) remains obscure. Here, we demonstrate that splenocytes from IL-21R−/− mice show attenuated GVHD symptoms as compared to splenocytes from wild type mice. In addition, the survival of mice receiving IL-21R−/− splenocytes is significantly longer than of those receiving wild type splenocytes. Both types of splenocytes appear to efficiently eliminate leukemic cells, suggesting the retention of GVL effects. Our results suggest that CD4 T-cells augment GVHD by autocrine stimulation via IL-21, and that production of IL-17 is downregulated in IL-21R−/− splenocyte recipients. To develop a treatment model in mice, we generated a decoy receptor for IL-21, in which most of the intracellular domain is deleted. Mice receiving bone marrow cells transduced with this decoy receptor survived longer than those receiving cells transduced with an empty retrovirus.These results suggest that IL-21 promotes GVHD and that the blockade of IL- 21 signaling might be a useful treatment for GVHD, without causing loss of the GVL effect.

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