High-density presentation of an immunodominant minimal peptide on B cells is MHC-linked to Th1-like immunity

Abstract

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.