Point mutation of a rubella virus E1 protein T-cell epitope by substitution of single amino acid reversed the restrictive HLA-DR polymorphism: a possible mechanism maintaining HLA polymorphism.
The influence of single amino acid substitutions within a rubella E1 protein T-cell epitope, E1(273-284) on T-cell recognition was studied. Substitutions of an uncharged amino acid A for an E or for a T and substitution of a T for S were found to not significantly reduce the T-cell responses. However, substitution of a charged residue such as E for hydrophobic residues (I, V, or W); D for Q; or a relatively larger size amino acid for polar residues completely abolished the cytotoxicities mediated by E1(273-284)-specific T-cell clone. A set of single amino acid-substituted peptide analogs of E1(273-284) not eliciting cytotoxicity of the T-cell clone was used to test the influence of point mutation of the epitope on HLA DR restrictions. A panel of B-cell lines with different DR4 subtypes was used as targets in cytotoxicity assays to determine the restrictive HLA molecules. Results showed that modification of the T-cell epitope by point mutation could reverse the HLA DR restriction from one allele to other alleles. A model based on these results has been proposed to explain the mechanism balancing major histocompatibility complex (MHC) polymorphism in outbred populations.
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Department of Paediatrics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
Mitchell
L A
LA
Décarie
D
D
Tingle
A J
AJ
Lacroix
M
M
Zrein
M
M
D019943:Amino Acid Substitution; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D017354:Point Mutation; D011110:Polymorphism, Genetic; D012412:Rubella virus / Q000235:genetics / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D014759:Viral Envelope Proteins; C061826:E1 envelope protein, Rubella virus