title: Expression of CD1d by myelomonocytic leukemias provides a target for cytotoxic NKT cells.
abstract: Natural killer T (NKT) cells with an invariant T-cell receptor for alpha-galactosylceramide (alphaGalCer) that is presented by CD1d have been reported to be cytotoxic for myelomonocytic leukemia cells. However, the necessity for leukemia cell CD1d expression, the role of alphaGalCer, and the cytotoxic mechanisms have not been fully elucidated. We evaluated these issues with myeloid leukemia cells from 14 patients and purified NKT cells that were alphaGalCer/CD1d reactive. CD1d was expressed by 80-100% of cells in three of seven acute myeloid leukemias (AMLs) and by 28-77% of cells in five of six juvenile myelomonocytic leukemias (JMML). CD1d+ AML cells were myelomonocytic or monoblastic types, and CD1d+ JMML cells were differentiated and CD34-. Cytotoxicity required leukemia cell CD1d expression and was increased by alphaGalCer (P<0.0001) and inhibited by anti-CD1d mAb (P<0.001). The perforin/granzyme-B pathway of NKT cells caused up to 85% of cytotoxicity, and TNF-alpha, FASL, and TRAIL mediated additional killing. CD56+ NKT cells expressed greater perforin and were more cytotoxic than CD56 NKT cells without alphaGalCer (P<0.0001), but both subpopulations were highly and equally cytotoxic in the presence of alphaGalCer. We conclude that CD1d expression is stage-specific for myelomonocytic leukemias and could provide a target for NKT-cell-mediated immunotherapy.
authors.affiliation: Division of Hematology-Oncology, Department of Pediatrics, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA.
authors.forename: L S
authors.initials: LS
authors.lastname: Metelitsa
authors.forename: K I
authors.initials: KI
authors.lastname: Weinberg
authors.forename: P D
authors.initials: PD
authors.lastname: Emanuel
authors.forename: R C
authors.initials: RC
authors.lastname: Seeger
mesh_terms: D018949:Antigens, CD1 / Q000378:metabolism*; D055610:Antigens, CD1d; D001853:Bone Marrow / Q000473:pathology; D019002:CD56 Antigen / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005699:Galactosylceramides / Q000494:pharmacology*; D020869:Gene Expression Profiling; D053804:Granzymes; D006801:Humans; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000276:immunology*; D015479:Leukemia, Myelomonocytic, Acute / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012697:Serine Endopeptidases / Q000378:metabolism; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D018949:Antigens, CD1; D055610:Antigens, CD1d; C526877:CD1D protein, human; D019002:CD56 Antigen; D005699:Galactosylceramides; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases