HLA-E protects glioma cells from NKG2D-mediated immune responses in vitro: implications for immune escape in vivo.
The nonclassical MHC class I molecule HLA-E is the only known ligand for CD94/NKG2A and CD94/NKG2C expressed on NK and CD8+ alphabeta and gammadelta T cells. HLA-E may transmit either activating signals via CD94/NKG2C or inhibitory signals mediated by CD94/NKG2A. Here we show that HLA-E is expressed at mRNA and protein level in human long-term glioma cell lines, primary ex vivo polyclonal glioblastoma cell cultures and surgical glioblastoma specimens. Furthermore, immunohistochemistry revealed an enhanced in vivo expression of HLA-E in gliomas of lower grades and a massive overexpression in grade IV glioblastomas compared with normal CNS tissue. An immune-inhibitory effect of HLA-E on tumor-specific CTL has already been described. We show that siRNA-mediated silencing of HLA-E or blocking of CD94/NKG2A enables NKG2D-mediated lysis of 51Cr-labeled tumor cells by NK cells. Thus, our study provides the first evidence that expression and interaction of HLA-E on cancer cells with CD94/NKG2A expressed on lymphocytes compromises innate anti-tumor immune responses.
Laboratory of Molecular Neuro-Oncology, Department of General Neurology, Hertie Institute for ClinicaI Brain Research, University of Tübingen Medical School, Tübingen, Germany. joerg.wischhusen@uni-tuebingen.de
Jörg
J
Wischhusen
Manuel A
MA
Friese
Michel
M
Mittelbronn
Richard
R
Meyermann
Michael
M
Weller
D015703:Antigens, CD / Q000494:pharmacology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000502:physiology; D005434:Flow Cytometry / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D005910:Glioma / Q000276:immunology* / Q000378:metabolism*; D006680:HLA Antigens / Q000235:genetics / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007694:Killer Cells, Natural / Q000378:metabolism; D055654:NK Cell Lectin-Like Receptor Subfamily C; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034741:RNA, Small Interfering / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D000097625:HLA-E Antigens
D015703:Antigens, CD; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D055654:NK Cell Lectin-Like Receptor Subfamily C; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D000097625:HLA-E Antigens; C527054:KLRC1 protein, human; C527059:KLRC2 protein, human; C527085:KLRK1 protein, human