Defective human leukocyte antigen class I-associated antigen presentation caused by a novel beta2-microglobulin loss-of-function in melanoma cells.
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.
Chang
Chien-Chung
CC
Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Ogino
Takeshi
T
Mullins
David W
DW
Oliver
Janine L
JL
Yamshchikov
Galina V
GV
Bandoh
Nobuyuki
N
Slingluff
Craig L
CL
Ferrone
Soldano
S
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
D015234:HLA-A Antigens; D001613:beta 2-Microglobulin