BINDING OF ALA-SUBSTITUTED ANALOGS OF HA306-320 TO DR1101, DR1301, AND DR0402 MOLECULES - CORRELATION OF DR-PEPTIDE INTERACTIONS WITH RECOGNITION BY A SINGLE TCR

We tested the hypothesis that a cross-reactive T-cell clone could reco gnize HA306-320 peptide complexed to autologous HLA-DR1101, and also t o allogenic HLA-DR0402 and HLA-DR1301 molecules, because of similar or ientations of HA306-320 side chains in the groove of the three DR mole cules. To approach peptide orientations in each HLA groove we compared the capacity of Ala-monosubstituted analogs to bind and be presented by DR1101, DR0402, and DR1301. Results indicated that the orientation of HA306-320 in DR1101 was grossly similar to the known orientation of HA307-319 in DR0101. Data suggested many similarities in peptide orie ntations in DR0402 and DR1301 as well. However, differences in binding were also observed. Ala substitution of Y309 had much less effect on peptide binding ro DR1301 and DR0402 than to DR1101 and Ala-substituti on of T314 increased affinity for DR1301 but not for DR1101 and DR0402 . These alterations of peptide-DR interactions were probably communica ted to the upper peptide surface. Indeed, the levels of T-cell clone r eactivities against analogs mutated at positions predicted to face the TCR were lower when complexed to allogeneic DR molecules than when co mplexed to DR1101. Yet these epitopic alterations are likely subtle, s ince the decreased reactivity of the clone to allogeneic molecules cou ld be compensated by peptide substitution at Y309, predicted to face t he MHC.