CONFORMATIONAL DIFFERENCES IN MAJOR HISTOCOMPATIBILITY COMPLEX-PEPTIDE COMPLEXES CAN RESULT IN ALLOREACTIVITY

Mutations within the class I major histocompatibility complex (MHC) mo lecule that affect a peptide binding can result in strong allogeneic r esponses. It is believed this reflects, in part, binding of a differen t set of endogenous peptides by each MHC molecule. We have examined th e representation of allopeptides recognized by K-b-specific cytotoxic T lymphocytes (CTL) clones among targets that express either the K-b O r the K-bm8 mutant. These class I molecules mutationally differ by sev eral residues at the base of the peptide binding groove resulting in l ack of recognition of bm8 targets by most K-b-specific CTL, and in str ong mutual alloreactivity. Since these differences involve pockets in the base of the peptide binding groove that are presumed to contribute to the affinity of peptide binding, and there is evidence for differe nces in peptide binding by the mutant and wild type molecule, it was c onsidered most likely that alloreactivity was due to binding of differ ent sets of peptides by each of these molecules. Surprisingly, the all opeptides recognized by K-b-specific clones from a variety of responde rs, including bm8, are often found associated with both the wild type and mutant class I molecules. Although for some allopeptides the amoun t of peptide normally found associated with bm8 is less than that asso ciated with K-b, reactivity could not be restored by increasing the am ount of the relevant peptide. Thus, the basis for much of the alloreac tivity observed in this particular mutant and wild type combination is not the presence or absence of the relevant allopeptide but rather th e different conformation adapted by the peptide-MHC complex. These res ults allow us to conclude that strong alloreactive responses can resul t from T cell recognition of conformational differences between the st imulation and responder MHC molecules.