The gallinaceous lysozymes are a family of antigens that are distantly related to mouse lysozyme. A T cell-dependent proliferation assay was used to characterize the spectrum of reactivities to lysozyme determinants in B10-congenic mice. Cross-reactivity studies using a panel of species variant lysozymes to stimulate lymph node cells from chicken egg white lysozyme- and ring-necked pheasant egg white lysozyme-primed B10.D2 mice indicated a preferential focusing of T cell reactivity onto a single determinant containing amino acids 113-114. These data, in conjunction with results obtained by priming with cyanogen bromide cleavage fragments of lysozymes, suggested that a site commmon to the L3 region (amino acids 106-129) of all the lysozymes tested was a preferential anchorage site for I region-encoded Ia molecules on H-2d antigen-presenting cells, leading to the limited display of a determinant containing residues 113-114. Priming with L2H (amino acids 13-105), a peptide containing the major epitopes recognized by B10. A and B10 mice, failed to stimulate any T cell proliferation by B10.D2 lymph node cells. Thus, it appears the Ia molecules in any one mouse strain attach to very few sites on lysozyme to effectively display antigenic determinants for T cell activation. This result points to a model of limited determinant selection even on a very "foreign" antigen based upon a shortage of appropriate amino acid residues usable by Ia antigen-presenting structures of a strain.