RAT MHC-LINKED PEPTIDE TRANSPORTER ALLELES STRONGLY INFLUENCE PEPTIDEBINDING BY HLA-B27 BUT NOT B27-ASSOCIATED INFLAMMATORY DISEASE

Rats transgenic for the human MHC molecule HLA-B27 were used to study the effect of two alleles, cim(a) and cim(b), which are associated wit h peptide transport by the MHC-encoded Tap2 transporter, on the functi on of HLA-B27 as a restriction element for CTL recognition of the male H-Y minor H Ag and on the multisystem inflammatory disease characteri stic of B27 transgenic rats, Anti-H-Y CTL generated in cim(a) B27 tran sgenic rats lysed male B27 cim(b/b) targets significantly less well th an cim(a/a) or cim(a/b) targets, Addition of exogenous H-Y peptides to male B27 cim(b/b) targets increased susceptibility to lysis to the le vel of cim(a/a) targets, Male B27 cim(b/b) cells were less efficient t han cim(a/a) cells in competitively inhibiting CTL lysis of female B27 cim(a/a) targets sensitized with exogenous H-Y peptides, H-3-Labeled peptides eluted from 827 molecules of lymphoblasts from rats of two ci m(b) and three cim(a) RT1 haplotypes showed that the cim(b) peptide po ol favors comparatively longer and/or more hydrophobic peptides, These results indicate that RT1-linked Tap2 polymorphism in the rat strongl y influences peptide loading of HLA-B27. Nonetheless, the prevalence a nd severity of multisystem inflammatory lesions were comparable in bac kcross rats bearing either cim(a/b) or cim(b/b). It thus appears eithe r that binding of specific peptides to B27 is unimportant in the patho genesis of B27-associated disease or that the critical peptides, unlik e H-Y and many others, are not influenced by Tap transporter polymorph ism.