AbstractThe immunological reactivity against the N‐terminal region of hen egg‐white lysozyme (HEL) has been investigated by a synthetic peptide (PHEL) comprising residue 1–18 of HEL and by an analogue peptide (PREL) in which phenylalanine at position 3 is substituted by tyrosine. Both peptides are immunogenic in (C57BL/10 × DBA/2)F1mice genetically responder to HEL. In C57BL/6 mice, genetically nonresponder to HEL, PRELinduces anti‐peptide antibodies that also bind to PHELwhereas PHELis not immunogenic.Thus, a single amino acid substitution in a synthetic peptide converts a nonresponder mouse strain into a responder one. Anti‐PHELantibodies demonstrate a higher binding to HEL than anti‐PRELantibodies, indicating that phenylalanine at position 3 is important for induction of anti‐peptide antibodies able to recognize native HEL. At the T cell level the two peptides show very high bidirectional cross‐reactivity between themselves and with HEL for interleukin 2 production, antigen‐specific proliferation and delayed‐type hypersensitivity response, whereas conservation of phenylalanine at position 3 is required for induction of suppressor cells cross‐reactive with HEL. This indicates that the N‐terminal region of HEL contains epitope(s) able to induce the same level of helper T cell activity as the native HEL molecule. However, helper T cells do not discriminate between PHELand PRELwhereas phenylalanine at position 3 is critical for HEL‐specific s