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Polymorphism in the α3 domain of HLA-A molecules affects binding to CD8

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Abstract

CYTOTOXIC T lymphocytes (CTL) expressing the CD8 glycoprotein recognize peptide antigens presented by class I major histocompatibility complex (MHC) molecules1,2. 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 (ref. 3). 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.l 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 α3 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 α3 domain of class I MHC molecules.

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Authors and Affiliations

  1. Department of Cell Biology, Stanford University, Stanford, California, 94305, USA

    Russell D. Salter, Benjamin P. Chen & Peter Parham

  2. Department of Pediatrics, Stanford University, Stanford, California, 94305, USA

    Carol Clayberger & Alan M. Krensky

  3. Department of Microbiology and Immunology, University of California at San Francisco, California, 94143, USA

    Anne M. Norment & Dan R. Littman

  4. Howard Hughes Medical Institute, University of California at San Francisco, California, 94143, USA

    Dan R. Littman

Authors
  1. Russell D. Salter
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  2. Anne M. Norment
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  3. Benjamin P. Chen
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  4. Carol Clayberger
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  5. Alan M. Krensky
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  6. Dan R. Littman
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  7. Peter Parham
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Salter, R., Norment, A., Chen, B. et al. Polymorphism in the α3 domain of HLA-A molecules affects binding to CD8. Nature 338, 345–347 (1989). https://doi.org/10.1038/338345a0

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