The development and the differentiation of CD8(+) T cells are dependent on IL-15. Here, we have studied the source and mechanism of how IL-15 modulates CD8(+) T cell-mediated Th1 immune responses by employing two delayed-type hypersensitivity (DTH) models. IL-15-deficient (IL-15(-/-)) mice or mice treated with soluble IL-15Ralpha as an IL-15 antagonist showed significantly reduced CD8(+) T cell-dependent DTH responses, while activation of CD4(+) T cell and B cell functions remained unaffected. Injection of antigen-labeled dendritic cells (DC) from IL-15(+/+), IL-15(-/-) or IL-15Ralpha(-/-) mice revealed that DC-derived IL-15 is an absolute requirement for the initiation of DTH response. The re-establishment of the interaction of IL-15 with the IL-15Ralpha by incubating IL-15(-/-) DC with IL-15 completely restored the capacity to prime T cells for DTH induction in vivo. Moreover, IL-15 also enhanced secretion of pro-inflammatory cytokines by DC and triggered in vitro CD8(+) T cell proliferation and IL-2 release. Taken together, the data suggest that an autocrine IL-15/IL-15Ralpha signaling loop in DC is essential for inducing CD8(+)-dependent Th1 immune responses in mice. Therefore, targeted manipulation of this loop promises to be an effective, novel strategy for therapeutic modulation of clinically relevant DTH reactions.