Human gammadelta T lymphocytes induce robust NK cell-mediated antitumor cytotoxicity through CD137 engagement.
Natural killer (NK) cells are innate effector lymphocytes that control the growth of major histocompatibility complex class I negative tumors. We show here that γδ T lymphocytes, expanded in vitro in the presence isopentenylpyrophosphate (IPP), induce NK cell-mediated killing of tumors that are usually resistant to NK cytolysis. The induction of cytotoxicity toward these resistant tumors requires priming of NK cells by immobilized human immunoglobulin G1 and costimulation through CD137L expressed on activated γδ T lymphocytes. This costimulation increases NKG2D expression on the NK-cell surface, which is directly responsible for tumor cell lysis. Moreover, culturing peripheral blood mononuclear cells with zoledronic acid, a γδ T lymphocyte activating agent, enhances NK-cell direct cytotoxicity and antibody-dependent cellular cytotoxicity against hematopoietic and nonhematopoietic tumors. Our data reveal a novel function of human γδ T lymphocytes in the regulation of NK cell-mediated cytotoxicity and provide rationale for the use of strategies to manipulate the CD137 pathway to augment innate antitumor immunity.
Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, USA.
Amudhan
A
Maniar
Xiaoyu
X
Zhang
Wei
W
Lin
Brian R
BR
Gastman
C David
CD
Pauza
Scott E
SE
Strome
Andrei I
AI
Chapoval
D053330:4-1BB Ligand / Q000276:immunology / Q000378:metabolism; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D051940:B7-2 Antigen / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003469:Culture; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology / Q000473:pathology; D053278:OX40 Ligand / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology* / Q000378:metabolism
D053330:4-1BB Ligand; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D007074:Immunoglobulin G; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D053278:OX40 Ligand; D016692:Receptors, Antigen, T-Cell, gamma-delta; C089251:TNFSF4 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9