Polymorphism in the alpha 3 domain of HLA-A molecules affects binding to CD8.
Cytotoxic T lymphocytes (CTL) expressing the CD8 glycoprotein recognize peptide antigens presented by class I major histocompatibility complex (MHC) molecules. This correlation and the absence of CD8 polymorphism led to the hypothesis that CD8 binds to a conserved site of class I MHC molecules. Using a cell-cell binding assay we previously demonstrated specific interaction between human class I MHC (HLA-A,B,C) molecules and CD8. Subsequent analysis of the products of 17 HLA-A,B alleles revealed a natural polymorphism for CD8 binding in the human population. Two molecules, HLA-Aw68.1 and HLA-Aw68.2, which do not bind CD8, have a valine residue at position 245 whereas all other HLA-A,B,C molecules have alanine. Site-directed mutagenesis shows that this single substitution in the alpha 3 domain is responsible for the CD8 binding phenotype and also affects recognition by alloreactive and influenza-specific CTL. Our results indicate that CD8 binds to the alpha 3 domain of class I MHC molecules.
Salter
R D
RD
Department of Cell Biology, Stanford University, California 94305.
Norment
A M
AM
Chen
B P
BP
Clayberger
C
C
Krensky
A M
AM
Littman
D R
DR
Parham
P
P
D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism*; D005805:Genes, MHC Class I; D015234:HLA-A Antigens / Q000235:genetics*; D006801:Humans; D009154:Mutation; D011110:Polymorphism, Genetic
D000945:Antigens, Differentiation, T-Lymphocyte; D015234:HLA-A Antigens