Mice expressing hen egg-white lysozyme (HEL) as a transgene are unresponsive to immunization with the HEL protein. Profound tolerance was found even in situations where the amounts of I-A^k-peptide complexes was 100 or less per APC. Among the few T cells that escaped tolerance, we did not observe differential responses to the different HEL epitopes, perhaps because of the very high sensitivity of the negative selection process. The same HEL transgenic mice that did not respond to HEL responded to immunization with the 46–61 peptide of HEL. These peptide-specific T cells that escaped negative selection belonged to a set that reacted with a particular conformer of the HEL peptide-I-A^k (type B). The presence of type B reactive T cells should be considered in autoimmunity.