The tumor suppressor TSLC1/NECL-2 triggers NK-cell and CD8+ T-cell responses through the cell-surface receptor CRTAM.
The tumor suppressor in lung cancer-1 (TSLC1) gene is frequently silenced in human lung carcinomas, and its expression suppresses tumorigenesis in nude mice. TSLC1 encodes a cell-surface protein called Necl-2 that belongs to the Nectin and Nectin-like (Necl) family of molecules. Necl-2 mediates epithelial cell junctions by homotypic contacts and/or heterotypic interactions with other Nectins and Necls. Thus, it inhibits tumorigenesis by ensuring that epithelial cells grow in organized layers. Here, we demonstrate that natural killer (NK) cells and CD8+ T cells recognize Necl-2 through a receptor known as class I-restricted T-cell-associated molecule (CRTAM), which is expressed only on activated cells. CRTAM-Necl-2 interactions promote cytotoxicity of NK cells and interferon gamma (IFN-gamma) secretion of CD8+ T cells in vitro as well as NK cell-mediated rejection of tumors expressing Necl-2 in vivo. These results provide evidence for an additional mechanism of tumor suppression mediated by TSLC1 that involves cytotoxic lymphocytes. Furthermore, they reveal Necl-2 as one of the molecular targets that allows the immunosurveillance network to distinguish tumor cells from normal cells.
Boles
Kent S
KS
Washington University School of Medicine, 660 S. Euclid, St Louis, MO 63110, USA.
Barchet
Winfried
W
Diacovo
Tom
T
Cella
Marina
M
Colonna
Marco
M
D000818:Animals; D001665:Binding Sites; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D015166:Monitoring, Immunologic; D009369:Neoplasms / Q000276:immunology; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins
C403514:CADM1 protein, human; C498598:Cadm1 protein, mouse; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C408522:class-I restricted T cell-associated molecule; D007371:Interferon-gamma