H-2b mice produce insulin-specific antibody when injected with bovine but not porcine or human insulin. Nevertheless, CD4+ T cells have been cloned from C57BL/6 mice primed with porcine, human, and bovine insulin. Here we tested the hypothesis that CD4+ T cells from C57BL/6 mice primed with porcine or human insulin are functionally distinct from those primed with bovine insulin. Our results show that variants of insulin that stimulate antibody responses induced Th2 clones, whereas variants of insulin that fail to stimulate antibody induced Th0 clones. Th0 clones triggered delayed-type hypersensitivity (DTH) in adoptive recipients, whereas Th2 clones did not. Insulin variants that primed Th0 clones also directly primed for DTH responses, while variants that activated Th2 clones did not. Thus, induction of Th2 clones correlated with the ability of mice to make antibody responses to insulin while development of Th0 clones correlated with DTH responses and the failure to produce antibody.