Rat MHC-linked peptide transporter alleles strongly influence peptide binding by HLA-B27 but not B27-associated inflammatory disease

William A. Simmons, Louise Y W Leong, Nimman Satumtira, Geoffrey W. Butcher, Jonathan C. Howard, James A Richardson, Clive A. Slaughter, Robert E Hammer, Joel D Taurog

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Abstract

Rats transgenic for the human MHC molecule HLA-B27 were used to study the effect of two alleles, cima and cimb, 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 cima 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 cimb and three cima RT1 haplotypes showed that the cimb 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.

Original languageEnglish (US)
Pages (from-to)1661-1667
Number of pages7
JournalJournal of Immunology
Volume156
Issue number4
StatePublished - Feb 15 1996

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HLA-B27 Antigen
Alleles
Peptides
Transgenic Rats
peptide permease
Haplotypes

ASJC Scopus subject areas

  • Immunology

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Rat MHC-linked peptide transporter alleles strongly influence peptide binding by HLA-B27 but not B27-associated inflammatory disease. / Simmons, William A.; Leong, Louise Y W; Satumtira, Nimman; Butcher, Geoffrey W.; Howard, Jonathan C.; Richardson, James A; Slaughter, Clive A.; Hammer, Robert E; Taurog, Joel D.

In: Journal of Immunology, Vol. 156, No. 4, 15.02.1996, p. 1661-1667.

Research output: Contribution to journalArticle

Simmons, William A. ; Leong, Louise Y W ; Satumtira, Nimman ; Butcher, Geoffrey W. ; Howard, Jonathan C. ; Richardson, James A ; Slaughter, Clive A. ; Hammer, Robert E ; Taurog, Joel D. / Rat MHC-linked peptide transporter alleles strongly influence peptide binding by HLA-B27 but not B27-associated inflammatory disease. In: Journal of Immunology. 1996 ; Vol. 156, No. 4. pp. 1661-1667.
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abstract = "Rats transgenic for the human MHC molecule HLA-B27 were used to study the effect of two alleles, cima and cimb, 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 cima 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 cimb and three cima RT1 haplotypes showed that the cimb 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.",
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AU - Leong, Louise Y W

AU - Satumtira, Nimman

AU - Butcher, Geoffrey W.

AU - Howard, Jonathan C.

AU - Richardson, James A

AU - Slaughter, Clive A.

AU - Hammer, Robert E

AU - Taurog, Joel D

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