High peptide affinity for MHC class I does not correlate with immunodominance

Cytotoxic T (Tc)-cell responses against influenza virus infection in BALB/c (H-2(d)) mice are dominated by Tc clones reactive to the viral nucleoprotein (NP). Here, we report investigations using recombinant vaccinia viruses (VV) encoding major histocompatibility complex (MHC) class I H-2K(d) molecules differing by a single amino acid from glutamine (wild-type, K(dw)) to histidine (mutant, K(dm)) at position 114 located in the floor of the peptide-binding groove. Influenza-infected target cells expressing K(dw) were strongly lysed by K(d)-restricted Tc cells against A/WSN influenza virus or the immunodominant peptide of viral NP (NPP^147-155), whereas infected K(dm)-expressing targets gave little or no lysis, respectively, thus showing the immunodominance of NPP^147-155. K(dm)-expressing target cells saturated with synthetic NPP^147-155 (10^-5M) were lysed similarly to K(dw)-expressing targets by NPP^147-155-specific Tc cells. Thus the defect in influenza-infected K(dm)-expressing targets was quantitative; insufficient K(dm)-peptide complexes were expressed. Tc-cell responses against four other viruses or alloantigens showed no effect of K(dm). When peptide transport-defective cells were infected with VV-K(dw) or VV-K(dm) and co-infected with a recombinant VV encoding an endoplasmic reticulum-targeted viral peptide, two influenza haemaglutinin peptides caused higher expression of K(dw) than NPP^147-155 indicating their higher affinity for K(dw). These results are inconsistent with the hypothesis that immunodominance in the anti-influenza response reflects high affinity of the immunodominant peptide, but are consistent with skewing of the Tc-cell receptor repertoire.