Introduction: Induction of (auto)immune responses by drugs or environmental chemicals requires costimulatory signals in addition to release of (auto)antigens. Previous studies have indicated that chemicals can induce this costimulation, and that the type of response elicited is influenced by genotype and relates to susceptibility to the adverse immune effects of the compound. Here, we assessed the modulatory role of the stimulating chemical itself.Materials and Methods: The prototype autoimmunogenic chemicals streptozotocin (STZ) and HgCl 2 that induce distinct adverse immune effects in the same mouse strain, were co-injected with the reporter antigen TNP-OVA into the footpad of BALB/c mice. Next, the type of immune response elicited to the reporter antigen was assessed by (intra-cellular) flowcytometry, TNP-specific ELISPOT assays, and immuno histochemistry.Results: A single injection of STZ induced an increase of IFN-γ producing Th (CD4 + ) and Tc (CD8 + ) cells in the draining lymph node (data on IL-4 and IL-10 producing cells are pending). Moreover, the total number of CD4 + cells was decreased, whereas CD8 + cells, macrophages and apoptotic cells were increased in conjunction with enhanced IgG 2 a and IgG 2 b production to TNP-OVA. Injection of HgCl 2 on the other hand, reduced the number of IFN-γ producing cells, induced accumulation of B cells and of CD4 + and CD8 + T cells, enhanced IgG 1 and IgE production to TNP-OVA, and primed for secondary IgG 1 and IgE production as well as for DTH reactions.Conclusion: Together these results indicate that STZ stimulates type-1 responses, whereas HgCl 2 enhances mixed type-1 and 2 responses in BALB/c mice. Importantly, these responses stimulated by a single injection of chemical match the (auto)immune effects elicited to unknown (auto) antigens following multiple injections of these compounds, suggesting that induction of selective costimulation by chemicals is an important factor provoking the onset of autoimmunity in susceptible individuals.