Natural splice variant of MHC class I cytoplasmic tail enhances dendritic cell-induced CD8+ T-cell responses and boosts anti-tumor immunity

PLoS One. 2011;6(8):e22939. doi: 10.1371/journal.pone.0022939. Epub 2011 Aug 10.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alternative Splicing / genetics*
  • Alternative Splicing / immunology
  • Animals
  • Antigen Presentation / genetics
  • Antigen Presentation / immunology
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cytoplasm / metabolism*
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology*
  • Epitopes / genetics
  • Epitopes / immunology
  • Exons / genetics
  • HLA Antigens / chemistry*
  • HLA Antigens / genetics*
  • HLA Antigens / immunology
  • Humans
  • Lentivirus / genetics
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / immunology*
  • Mice
  • Sequence Deletion / immunology
  • T-Lymphocytes, Cytotoxic / cytology
  • T-Lymphocytes, Cytotoxic / immunology


  • Epitopes
  • HLA Antigens