Nickel induces secretion of IFN-gamma by splenic natural killer cells

Although nickel hypersensitivity is known as a delayed-type hypersensitivity mediated by nickel-specific T cells, it is greatly influenced by other immune cells. Here we show that splenic natural killer cells (NK cells) directly or indirectly respond to nickel by secretion of IFN-gamma. Using enzyme-linked immunosorbent spot (ELISPOT) assays, we found that nickel-reactive cells readily secreted IFN-gamma when splenocytes were cultured in the presence of varying concentrations of nickel sulfate (NiSO(4)) for 24 h. However, nickel-reactive IL-2- or IL- 4-secreting cells were infrequent during the 24-h culture with NiSO(4). Immune responses to nickel were innate, not adaptive, in nature since the frequency of nickel-reactive IFN-g-secreting cells did not increase upon previous exposure to NiSO(4) and recombination activating gene (RAG)-1-deficient mice contained nickel-reactive IFN-gamma-secreting cells. The involvement of NK cells in the innate response to NiSO(4) was confirmed since we could observe a significant reduction of the frequency of nickel-reactive cells in NK cell-depleted mice. Furthermore, the number of IFN-gamma secreting cells was significantly reduced in the ELISPOT assays when NKG2D was blocked by anti-NKG2D antibody. These results suggest that there is an early and rapid innate immune response to nickel, which is mediated by NK cells and the NKG2D receptor. The significance of the innate response to nickel is that it may contribute to development of the late T cell-mediated delayed type hypersensitivity against nickel.