BACKGROUND: Immunologic mechanisms of desensitization are still incompletely understood. Safer methods of immunotherapy with reduced risks of anaphylaxis need to be developed. OBJECTIVE: To study the effects of conventional venom immunotherapy (VIT) on phospholipase A2(PLA2)-specific T cells and on T-cell reactivity to short and long synthetic peptides that map the PLA2 molecule. METHOD: Proliferation of a CD4+ cell-enriched peripheral blood mononuclear cell fraction and cytokine secretion by T cell lines from patients hypersensitive to bee venom and undergoing VIT in response to PLA2 and PLA2 synthetic peptides were measured. RESULTS: T-cell proliferation in response to three synthetic peptides, 40 to 60 amino acids long and mapping the entire PLA2 molecule with an overlap of 10 residues (1 to 59, 51 to 99, and 90 to 134) steadily increased during the first 14 weeks of VIT corresponding to the treatment period with incremental doses of antigen. These results are in contrast to the low proliferation indices obtained with short (15 amino acid-long) peptides, and the inability to characterize the immunodominant region of the molecule with short peptides. At the end of VIT (after 3 to 5 years), there was correspondingly, a marked decrease in T cell responsiveness to PLA2 and to its long synthetic peptides. This response was paralleled by a shift in the pattern of cytokine secretion by T cell lines from a T(H0)-type to a T(H1)-type pattern. CONCLUSION: After a transient increase in T-cell proliferation, late VIT was characterized by T-cell hyporesponsiveness to allergen and by modulation of cytokine secretion from a T(H0)-type to a T(H1)-type pattern. Because of their capacity to recruit multiple T-cell epitopes, long peptides mapping the entire PLA2 molecule appear to be efficient T cell stimulators and may represent potential candidates for peptide immunotherapy.