title: Natural splice variant of MHC class I cytoplasmic tail enhances dendritic cell-induced CD8+ T-cell responses and boosts anti-tumor immunity.
abstract: Dendritic cell (DC)-mediated presentation of MHC class I (MHC-I)/peptide complexes is a crucial first step in the priming of CTL responses, and the cytoplasmic tail of MHC-I plays an important role in modulating this process. Several species express a splice variant of the MHC-I tail that deletes exon 7-encoding amino acids (Δ7), including a conserved serine phosphorylation site. Previously, it has been shown that Δ7 MHC-I molecules demonstrate extended DC surface half-lives, and that mice expressing Δ7-K(b) generate significantly augmented CTL responses to viral challenge. Herein, we show that Δ7-D(b)-expressing DCs stimulated significantly more proliferation and much higher cytokine secretion by melanoma antigen-specific (Pmel-1) T cells. Moreover, in combination with adoptive Pmel-1 T-cell transfer, Δ7-D(b) DCs were superior to WT-D(b) DCs at stimulating anti-tumor responses against established B16 melanoma tumors, significantly extending mouse survival. Human DCs engineered to express Δ7-HLA-A*0201 showed similarly enhanced CTL stimulatory capacity. Further studies demonstrated impaired lateral membrane movement and clustering of human Δ7-MHC-I/peptide complexes, resulting in significantly increased bioavailability of MHC-I/peptide complexes for specific CD8+ T cells. Collectively, these data suggest that targeting exon 7-encoded MHC-I cytoplasmic determinants in DC vaccines has the potential to increase CD8+ T-cell stimulatory capacity and substantially improve their clinical efficacy.
authors.affiliation: Departments of Melanoma Medical Oncology and Immunology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Tania G
authors.initials: TG
authors.lastname: Rodríguez-Cruz
authors.forename: Shujuan
authors.initials: S
authors.lastname: Liu
authors.forename: Jahan S
authors.initials: JS
authors.lastname: Khalili
authors.forename: Mayra
authors.initials: M
authors.lastname: Whittington
authors.forename: Minying
authors.initials: M
authors.lastname: Zhang
authors.forename: Willem
authors.initials: W
authors.lastname: Overwijk
authors.forename: Gregory
authors.initials: G
authors.lastname: Lizée
mesh_terms: D017398:Alternative Splicing / Q000235:genetics* / Q000276:immunology; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D003593:Cytoplasm / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005091:Exons / Q000235:genetics; D006680:HLA Antigens / Q000737:chemistry* / Q000235:genetics* / Q000276:immunology; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology*; D051379:Mice; D017384:Sequence Deletion / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology
chemical_list: D000939:Epitopes; D006680:HLA Antigens