SUMMARYIn previous studies from this laboratory the antigenic sites of lysozyme were found to be composed of spatially adjacent surface residues that are mostly distant in sequence (i.e. discontinuous sites). For synthetic mimicking of the sites, we introduced the concept of ‘surface‐simulation’ synthesis by which the binding site residues are linked directly via peptide bonds with appropriate spacing and directionality into a single peptide which does not exist in the protein but mimics a surface region of it. In the present report T cell recognition of the surface‐simulation synthetic antigenic sites has been explored in a mouse strain, B10.BR, that is a high responder to lysozyme. The discontinuous antigenic sites of lysozyme also had the capacity to stimulate proliferation of T cells driven by native lysozyme in long‐term cultures. Thus, in addition to the four continuous T sites that we have recently reported, T cell recognition of lysozyme also involves discontinuous sites. This is the first clear demonstration that, contrary to a long‐held impression, T cell recognition is not restricted only to sequence features, but can also be directed to protein discontinuous surface areas of high conformational