Subcutaneous immunization with hen egg-white lysozyme (HEL) in complete Freund's adjuvant induces, both in antibody responder and nonresponder mice, a classical delayed-type hypersensitivity (DTH) reaction evaluated as footpad swelling. This response can be specifically transferred to naive recipients by Lyt-1+2- T cells and passive transfer is restricted by genes mapping in or to the left of the I-A region of the H-2 complex. Fine antigenic specificity analysis shows that HEL-primed T cells mediating DTH recognize ring-necked pheasant egg-white lysozyme, a lysozyme closely related to HEL, but fail to respond to human lysozyme, differing from HEL at 40% amino acid residues. Complete cross-reactivity between native and denaturated (reduced and carboxymethylated) HEL is exhibited by T cells involved in the DTH response. Subcutaneous injection of HEL coupled to spleen cells is also able to induce antigen-specific and genetically restricted DTH responses whereas the same cells administered by i.v. or i.p. route induce predominantly suppressor T cell activation. These suppressor T cells specifically inhibit the induction phase of DTH reactivity to HEL.