Rat MHC-linked peptide transporter alleles strongly influence peptide binding 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 with peptide transport by the MHC-encoded Tap2 transporter, on the function of HLA-B27 as a restriction element for CTL recognition of the male H-Y minor H Ag and on the multisystem inflammatory disease characteristic of B27 transgenic rats. Anti-H-Y CTL generated in cim^a B27 transgenic rats lysed male B27 cim(b/b) targets significantly less well than 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 level of cim(a/a) targets. Male B27 cim(b/b) cells were less efficient than cim(a/a) cells in competitively inhibiting CTL lysis of female B27 cim(a/a) targets sensitized with exogenous H-Y peptides. ³H-Labeled peptides eluted from B27 molecules of lymphoblasts from rats of two cim^b and three cim^a RT1 haplotypes showed that the cim^b peptide pool favors comparatively longer and/or more hydrophobic peptides. These results indicate that RT1-linked Tap2 polymorphism in the rat strongly influences peptide loading of HLA-B27. Nonetheless, the prevalence and severity of multisystem inflammatory lesions were comparable in back-cross rats bearing either cim(a/b) or cim(b/b). It thus appears either that binding of specific peptides to B27 is unimportant in the pathogenesis of B27-associated disease or that the critical peptides, unlike H-Y and many others, are not influenced by Tap transporter polymorphism.