title: High peptide affinity for MHC class I does not correlate with immunodominance.
abstract: Cytotoxic T (Tc)-cell responses against influenza virus infection in BALB/c (H-2d) 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-2Kd molecules differing by a single amino acid from glutamine (wild-type, Kdw) to histidine (mutant, Kdm) at position 114 located in the floor of the peptide-binding groove. Influenza-infected target cells expressing Kdw were strongly lysed by Kd-restricted Tc cells against A/WSN influenza virus or the immunodominant peptide of viral NP (NPP147-155), whereas infected Kdm-expressing targets gave little or no lysis, respectively, thus showing the immunodominance of NPP147-155. Kdm-expressing target cells saturated with synthetic NPP147-155 (10-5 M) were lysed similarly to Kdw-expressing targets by NPP147-155-specific Tc cells. Thus the defect in influenza-infected Kdm-expressing targets was quantitative; insufficient Kdm-peptide complexes were expressed. Tc-cell responses against four other viruses or alloantigens showed no effect of Kdm. When peptide transport-defective cells were infected with VV-Kdw or VV-Kdm and co-infected with a recombinant VV encoding an endoplasmic reticulum-targeted viral peptide, two influenza haemaglutinin peptides caused higher expression of Kdw than NPP147-155 indicating their higher affinity for Kdw. 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.
authors.affiliation: Division of Immunology and Cell Biology, John Curtin School of Medical Research, Australian National University, Canberra, A.C.T. 2601, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Müllbacher
authors.forename: M
authors.initials: M
authors.lastname: Lobigs
authors.forename: J W
authors.initials: JW
authors.lastname: Yewdell
authors.forename: J R
authors.initials: JR
authors.lastname: Bennink
authors.forename: R
authors.initials: R
authors.lastname: Tha Hla
authors.forename: R V
authors.initials: RV
authors.lastname: Blanden
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016056:Immunodominant Epitopes; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology*; D007519:Isoantigens; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009154:Mutation; D009698:Nucleoproteins / Q000276:immunology* / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D011994:Recombinant Proteins / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics
chemical_list: D006183:H-2 Antigens; C024755:H-2K(K) antigen; D016056:Immunodominant Epitopes; D007519:Isoantigens; D009698:Nucleoproteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; C122116:nucleoprotein (147-155)