High-density presentation of an immunodominant minimal peptide on B cells is MHC-linked to Th1-like immunity.
Ligand-directed differences in the amount of peptide presented on a specific APC subset could influence the functional outcome of any given immune response. We have investigated this issue with a biochemically determined immunodominant peptide that is presented at a higher density on the APC of Th1 responders (I-As genotypes) than on the APC of Th2 responders (I-Ab genotypes). MHC-linked high peptide density is expressed on B lymphocytes, predominantly those that bear the B7-2 activation marker/costimulatory ligand. We further investigated the role of I-As-specific polymorphism with transfected cells bearing an R-->Q change at position-70 of A beta (found only in the I-As allele). Strikingly, I-Ab-restricted Th1 and Th2 clones proliferate at a peptide dose 10- to 100-fold lower than wild-type on transfected fibroblasts bearing this single s-like substitution in A beta b. Moreover, the shift in the clone dose response is sensitive to the peptide's C-terminus, as is MHC-linked Th1-like immunity to this peptide in vivo. Together, these data suggest that ligand-density can dictate Th1/Th2 selection via a single MHC polymorphism that determines the level of peptide presented to a given TCR on activated B cells.
Murray
J S
JS
Division of Biology, Kansas State University, Manhattan 66506, USA.
Kasselman
J P
JP
Schountz
T
T
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D001402:B-Lymphocytes / Q000276:immunology*; D018122:B7-1 Antigen / Q000378:metabolism; D002469:Cell Separation; D003094:Collagen / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006239:Haplotypes / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D016056:Immunodominant Epitopes / Q000032:analysis / Q000276:immunology*; D008239:Lysine / Q000276:immunology; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D011110:Polymorphism, Genetic / Q000276:immunology; D013154:Spleen / Q000166:cytology; D018417:Th1 Cells / Q000276:immunology*
D018122:B7-1 Antigen; D000949:Histocompatibility Antigens Class II; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D003094:Collagen; D008239:Lysine