title: Defective human leukocyte antigen class I-associated antigen presentation caused by a novel beta2-microglobulin loss-of-function in melanoma cells.
abstract: The major histocompatibility complex class I molecules consist of three subunits, the 45-kDa heavy chain, the 12-kDa beta(2)-microglobulin (beta(2)m), and an approximately 8-9-residue antigenic peptide. Without beta(2)m, the major histocompatibility complex class I molecules cannot assemble, thereby abolishing their transport to the cell membrane and the subsequent recognition by antigen-specific T cells. Here we report a case of defective antigen presentation caused by the expression of a beta(2)m with a Cys-to-Trp substitution at position 25 (beta(2)m(C25W)). This substitution causes misfolding and degradation of beta(2)m(C25W) but does not result in complete lack of human leukocyte antigen (HLA) class I molecule expression on the surface of melanoma VMM5B cells. Despite HLA class I expression, VMM5B cells are not recognized by HLA class I-restricted, melanoma antigen-specific cytotoxic T lymphocytes even following loading with exogenous peptides or transduction with melanoma antigen-expressing viruses. Lysis of VMM5B cells is restored only following reconstitution with exogenous or endogenous wild-type beta(2)m protein. Together, our results indicate impairment of antigenic peptide presentation because of a dysfunctional beta(2)m and provide a mechanism for the lack of close association between HLA class I expression and susceptibility of tumor cells to cytotoxic T lymphocytes-mediated lysis in malignant diseases.
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
authors.forename: Chien-Chung
authors.initials: CC
authors.lastname: Chang
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ogino
authors.forename: David W
authors.initials: DW
authors.lastname: Mullins
authors.forename: Janine L
authors.initials: JL
authors.lastname: Oliver
authors.forename: Galina V
authors.initials: GV
authors.lastname: Yamshchikov
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Bandoh
authors.forename: Craig L
authors.initials: CL
authors.lastname: Slingluff
authors.forename: Soldano
authors.initials: S
authors.lastname: Ferrone
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D017951:Antigen Presentation / Q000235:genetics*; D001483:Base Sequence; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D005805:Genes, MHC Class I / Q000276:immunology*; D015234:HLA-A Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000276:immunology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D001613:beta 2-Microglobulin / Q000235:genetics* / Q000276:immunology
chemical_list: D015234:HLA-A Antigens; D001613:beta 2-Microglobulin