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-Asgenotypes) than on the APC of Th2 responders (I-Abgenotypes). 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 Aβ (found only in the I-Asallele). 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 Aβb. Moreover, the shift in the clone dose response is sensitive to the peptideʹs C-terminus, as is MHC-linked Th1-like immunity to this peptidein 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.