The immunodominant CD4 T cell epitope of the bacteriophage lambda cI repressor protein in several inbred mouse strains can be represented by a peptide encompassing amino acids 12-26. Here, we show that this peptide, and a variety of its sequence variants, can induce immediate-type hypersensitivity in mice. 12-26 variants that differ by as little as single amino acid residues deviate greatly in their ability to induce hypersensitivity. Further, differences in major histocompatibility complex class II alleles appear to be as influential as changes in peptide structure in determining whether hypersensitivity is developed. The ability of a given peptide-class II combination to induce hypersensitivity correlates with production of peptide-specific antibody, but not with ability or inability to induce a T cell proliferative response. Administration of anti-interleukin 4 (IL-4) mAb prevents the development of hypersensitivity, and analysis of cytokine production by T cell hybridomas derived from peptide-immunized mice suggests that whether a given peptide-class II combination can induce hypersensitivity depends on its ability to induce IL-4 production. The data demonstrate that changes in the nature of the epitope(s) recognized by the CD4 T cell population can result in qualitative differences in the response elicited in this population, ultimately leading to dramatic quantitative and qualitative variations in the effector phase of the immune response.