AVOIDANCE OF SELF-REACTIVITY RESULTS IN SKEWED CTL RESPONSES TO RARE COMPONENTS OF SYNTHETIC IMMUNOGENS

In studying the CTL recognition of peptide determinants derived from t he nuclear Ag La (SS-B), we observed significant skewing of the respon se toward rare components present within the immunogen, Thus, priming of naive mouse lymphocytes in vitro with a synthetic H-2K(b)-binding p eptide comprising human La (hLa) residues 51-58 resulted in class I-re stricted cytotoxic T cells that failed to recognize naturally presente d hLa 51-58 peptide, Instead, the majority of T hybrids recognized a l ow abundance (less than or equal to 1%) contaminant present at picomol ar concentrations in the original synthesis and identified as a peptid e adduct containing N,4-t-butyl asparagine at position 6 of the hLa 51 -58 sequence, The preferred T cell recognition of the butyl adduct was not due to increased affinity of this peptide for the H-2K(b) molecul e or to the antagonism of CTL recognizing the unmodified determinant, Rather, the bias in the immune response appeared to be the result of p artial self-tolerance to the homologous mouse La 51-58 determinant, wh ich differs from its human counterpart by only a single amino acid at position 1 (T --> I). Accordingly, the CTL response appeared to be foc used on ''non-self'' ligands present within the synthesis, even though they were present at very low concentrations, These observations have significant implications for the use of synthetic peptide vaccines, e specially those designed to manipulate responses to self peptides such as tumor Ags in which self-tolerance may result in unexpected reactiv ity.