natural splice variant of mhc class i cytoplasmic tail enhances dendritic cell-induced cd8+ t-cell responses and boosts anti-tumor immunity我自然拼接的变体mhc类胞质尾增强树突状cell-induced cd8 + t细胞反应,促进抗肿瘤免疫力.pdfVIP

Natural Splice Variant of MHC Class I Cytoplasmic Tail Enhances Dendritic Cell-Induced CD8+ T-Cell Responses and Boosts Anti-Tumor Immunity ´ . . Tania G. Rodrıguez-Cruz , Shujuan Liu , Jahan S. Khalili, Mayra Whittington, Minying Zhang, Willem ´ Overwijk, Gregory Lizee* Departments of Melanoma Medical Oncology and Immunology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America 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 (D7), including a conserved serine phosphorylation site. Previously, it has been shown that D7 MHC-I molecules demonstrate extended DC surface half-lives, and that mice expressing D7-Kb generate significantly augmented CTL responses to viral challenge. Herein, we show that D7-Db-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, D7-Db DCs were superior to WT-Db DCs at stimulating anti-tumor responses against established B16 melanoma tumors, significantly extending mouse survival. Human DCs engineered to express D7-HLA-A*0201 showed similarly enhanced CTL stimulatory capacity. Further studies demonstrated impaired lateral membrane movement and clustering of human D7-MHC-I/peptide complexes, resulting in significantly increased bioavailability of MHC-I/pe