Interleukin-18 (IL-18), a unique cytokine that stimulates both T helper 1 (Th1) and Th2 responses, is associated with acute graft-versus-host disease (aGVHD), the major limiting toxicity following allogeneic stem cell transplantation. Here, we investigated the mechanism underlying the upregulation of IL-18 receptor (IL-18R) expression on T cells in murine aGVHD models. The induction of aGVHD elevated host serum IL-12 levels and increased expression of IL-18Ralpha chain (IL-18Ralpha) on engrafted T cells, in particular on CD8+ T cells. However, IL-18Ralpha expression did not increase on the CD4+ T cells of an IL-12-deficient host, indicating the IL-12-dependent upregulation of IL-18Ralpha expression on CD4+ T cells during aGVHD. Purified donor CD8+ T cells transferred in the host increased IL-18Ralpha expression. In vitro experiments showed that IL-18Ralpha expression upregulated on CD8+ T cells but not on CD4+ T cells on stimulation through the T cell receptor (TCR). These results suggest that IL-18Ralpha expression is differentially upregulated between CD4+ and CD8+ T cells during aGVHD, depending on endogenous IL-12 and TCR engagement, respectively.