Defects in antigen presentation of mutant influenza haemagglutinins are reversed by mutations in the MHC class II molecule.
A functional analysis was undertaken of the effects of mutating single amino acid residues in the alpha chain of the I-Ak molecule (to alanine; residues 50-79) on the ability of I-Ak transfectants to process and present influenza haemagglutinin to CD4+ T cell clones specific for two major antigenic sites of the HA1 subunit. In each instance, T cells were insensitive to a majority of substitutions in Ak with the exception of a few critical residues that differed for individual T cell clones. But more significantly, the failure of T cell clones to respond to mutant influenza viruses, containing drift substitutions within a T cell recognition site, in association with wild type I-Ak, could be reversed by single substitutions in Ak alpha. A T cell clone specific for HA1 120-139 failed to respond to a laboratory mutant virus (HA1 135 Gly----Arg) whereas optimal responses were observed with a mutant Ak transfectant (Ak alpha 56 Arg----Ala). Similarly, mutant transfectant 62 (Ak alpha 62 Gly----Ala) was able to present a natural variant virus A/TEX/77 to a T cell clone specific for HA1 48-67. We propose that Ak alpha 56 and Ak alpha 62 increase the affinity of association of mutant HA1 peptides for class II and therefore confer T cell recognition of variant viruses.
Warren
A P
AP
Laboratoire de Génétique Moléculaire des Eucaryotes du CNRS, Faculté de Médécine II Rue Humann, Strasbourg, France.
Paschedag
I
I
Benoist
C
C
Peccoud
J
J
Mathis
D
D
Thomas
D B
DB
D000595:Amino Acid Sequence; D000818:Animals; D015704:CD4 Antigens / Q000276:immunology; D002999:Clone Cells; D005802:Genes, MHC Class II; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006389:Hemagglutinins, Viral / Q000235:genetics* / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology; D007377:Interleukin-3 / Q000096:biosynthesis; D007739:L Cells / Q000276:immunology; D051379:Mice; D008808:Mice, Inbred CBA; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010449:Peptide Mapping; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection; D014357:Trypsin; D014759:Viral Envelope Proteins / Q000235:genetics
D015704:CD4 Antigens; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006389:Hemagglutinins, Viral; D000949:Histocompatibility Antigens Class II; D007377:Interleukin-3; D014759:Viral Envelope Proteins; D014357:Trypsin