Epitopes described in "Secondary anchor polymorphism in the HA-1 minor histocompatibility antigen critically affects MHC stability and TCR recognition."

Article Authors:Sarah Nicholls; Karen P Piper; Fiyaz Mohammed; Timothy R Dafforn; Stefan Tenzer; Mahboob Salim; Premini Mahendra; Charles Craddock; Peter van Endert; Hansjörg Schild; Mark Cobbold; Victor H Engelhard; Paul A H Moss; Benjamin E Willcox
Article Title:Secondary anchor polymorphism in the HA-1 minor histocompatibility antigen critically affects MHC stability and TCR recognition.
Reference Detail
Reference ID:1019711
Abstract:T cell recognition of minor histocompatibility antigens (mHags) underlies allogeneic immune responses that mediate graft-versus-host disease and the graft-versus-leukemia effect following stem cell transplantation. Many mHags derive from single amino acid polymorphisms in MHC-restricted epitopes, but our understanding of the molecular mechanisms governing mHag immunogenicity and recognition is incomplete. Here we examined antigenic presentation and T-cell recognition of HA-1, a prototypic autosomal mHag derived from single nucleotide dimorphism (HA-1(H) versus HA-1(R)) in the HMHA1 gene. The HA-1(H) peptide is restricted by HLA-A2 and is immunogenic in HA-1(R/R) into HA-1(H) transplants, while HA-1(R) has been suggested to be a "null allele" in terms of T cell reactivity. We found that proteasomal cleavage and TAP transport of the 2 peptides is similar and that both variants can bind to MHC. However, the His>Arg change substantially decreases the stability and affinity of HLA-A2 association, consistent with the reduced immunogenicity of the HA-1(R) variant. To understand these findings, we determined the structure of an HLA-A2-HA-1(H) complex to 1.3A resolution. Whereas His-3 is accommodated comfortably in the D pocket, incorporation of the lengthy Arg-3 is predicted to require local conformational changes. Moreover, a soluble TCR generated from HA-1(H)-specific T-cells bound HA-1(H) peptide with moderate affinity but failed to bind HA-1(R), indicating complete discrimination of HA-1 variants at the level of TCR/MHC interaction. Our results define the molecular mechanisms governing immunogenicity of HA-1, and highlight how single amino acid polymorphisms in mHags can critically affect both MHC association and TCR recognition.
Affiliations:Cancer Research UK Institute for Cancer Studies, Edgbaston, Birmingham B15 2TT, United Kingdom.
Reference Type:Literature
PubMed ID:19234124
Journal:Proc Natl Acad Sci U S A
Journal Volume:106
Article Pages:3889-94
Journal ISSN:0027-8424
Article Chemical List:Epitopes;HLA-A2 Antigen;Minor Histocompatibility Antigens;Receptors, Antigen, T-Cell;TAP1 protein, human;Arginine;Proteasome Endopeptidase Complex
Article MeSH List:ATP-Binding Cassette Transporters(metabolism); Arginine(metabolism); Cell Separation; Circular Dichroism; Crystallography, X-Ray; Epitopes(chemistry; immunology); HLA-A2 Antigen(chemistry); Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive(immunology); Minor Histocompatibility Antigens(chemistry; genetics); Polymorphism, Genetic; Proteasome Endopeptidase Complex(metabolism); Protein Binding; Protein Stability; Protein Structure, Secondary; Protein Transport; Receptors, Antigen, T-Cell(chemistry; immunology); Surface Plasmon Resonance; T-Lymphocytes, Cytotoxic(immunology); Tissue Donors
Curation Last Updated:2015-06-05 02:11:19