Defective Human Leukocyte Antigen Class I-associated Antigen Presentation Caused by a Novel β2-Microglobulin Loss-of-function in Melanoma Cells

• Published in: The Journal of biological chemistry 2006-07, Vol.281 (27), p.18763-18773
• Main Authors: Chang, Chien-Chung, Ogino, Takeshi, Mullins, David W., Oliver, Janine L., Yamshchikov, Galina V., Bandoh, Nobuyuki, Slingluff, Craig L., Ferrone, Soldano
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M511525200

The major histocompatibility complex class I molecules consist of three subunits, the 45-kDa heavy chain, the 12-kDa β2-microglobulin (β2m), and an ∼8-9-residue antigenic peptide. Without β2m, 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 β2m with a Cys-to-Trp substitution at position 25 (β2mC25W). This substitution causes misfolding and degradation of β2mC25W 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 β2m protein. Together, our results indicate impairment of antigenic peptide presentation because of a dysfunctional β2m 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.