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 (NpP147-155), whereas infected K-dm-expressing targets gave little or no lysis, respectively, thus showing the immunodominance of NPP147-155. K-dm-expressing target cells saturated with synthetic Npp(147-155) (10(-5) M) were lysed similarly to K-dw-expressing targets by NPP147-155-specific Tc cells. Thus the defect in influenza-infected Kdm-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 NPP147-155 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.