INDUCTION OF CROSS-REACTIVITY IN AN ENDOGENOUS VIRAL PEPTIDE NONREACTIVE TO FBL-3 TUMOR-SPECIFIC HELPER T-CELL CLONES

We previously reported a helper T-cell (Th) epitope (peptide i) which corresponded to the sequence ranging from positions 462 to 479 from th e N-terminus of the Friend-murine leukemia virus (F-MuLV) envelope pro tein (env(462-479)). Homologous sequences exist in both Moloney-murine leukemia (M-MuLV env(452-469)) and endogenous AKV (AKV env(453-470)) viruses, which differ from F-MuLV env(462-479) in 5 and 7 amino acids, respectively. However, peptide i-specific Th clones did not respond t o either of the corresponding exogenous or endogenous peptides, One am ino acid substitution in M-MuLV env(452-469) (Asn to Tyr at position 4 65: N465Y) and three amino acids in AKV env453-470 (H460S, A466Y and Y 468H) endowed both peptides with the reactivity to one of the Th clone s, F5-5, almost to the same degree as peptide i. However, the other Th clones responded differently to each of the modified endogenous pepti des substituted by one to three amino acids. The cells responsive to t he cross-reactive peptides occupied only a minor portion, if any, of t he bulk cultured lymph node cells from peptide i-immune mice, and in p articular, no significant response to the modified endogenous peptides was observed in repeated experiments. The exchange of at least 3 resi dues was necessary for the endogenous peptide to acquire sufficient cr oss-reactivity to two of the three Th clones. However, it was noticeab le that a single substitution of alanine by tyrosine at the dominant T -cell receptor (TCR) contact position of the peptide i, generated a we ak but significant cross-reactivity to one of the three Th clones in t his study. Thus, peptides of endogenous retroviral origin that would b e modified by mutational events might become 'non-self' and prime Th c ells leading to auto-antibody production and resulting in autoimmune d isease.