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, 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 cimb/b targets significantly less well than cima/a or cima/b targets. Addition of exogenous H-Y peptides to male B27 cimb/b targets increased susceptibility to lysis to the level of cima/a targets. Male B27 cimb/b cells were less efficient than cima/a cells in competitively inhibiting CTL lysis of female B27 cima/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 backcross rats bearing either cima/b or cimb/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.
Simmons
W A
WA
Harold C. Simmons Arthritis Research Center, University of Texas Southwestern Medical Center, Dallas 75235, USA.
Leong
L Y
LY
Satumtira
N
N
Butcher
G W
GW
Howard
J C
JC
Richardson
J A
JA
Slaughter
C A
CA
Hammer
R E
RE
Taurog
J D
JD
D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000483:Alleles; D000818:Animals; D030801:Animals, Genetically Modified; D000938:Antigen-Presenting Cells / Q000276:immunology; D005260:Female; D006182:H-Y Antigen / Q000276:immunology*; D015796:HLA-B27 Antigen / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology*; D008285:Major Histocompatibility Complex; D008297:Male; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D012216:Rheumatic Diseases / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D001613:beta 2-Microglobulin / Q000378:metabolism
D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D006182:H-Y Antigen; D015796:HLA-B27 Antigen; D010455:Peptides; C489514:Tap2 protein, rat; D001613:beta 2-Microglobulin; C071692:TAP2 protein, human