A critical role for natural killer T cells in immunosurveillance of methylcholanthrene-induced sarcomas.
Natural killer (NK) T cells initiate potent antitumor responses when stimulated by exogenous factors such as interleukin (IL)-12 or alpha-galactosylceramide (alpha-GalCer), however, it is not clear whether this reflects a physiological role for these cells in tumor immunity. Through adoptive transfer of NK T cells from wild-type to NK T cell-deficient (T cell receptor [TCR] Jalpha281-/-) mice, we demonstrate a critical role for NK T cells in immunosurveillance of methylcholanthrene (MCA)-induced fibrosarcomas, in the absence of exogenous stimulatory factors. Using the same approach with gene-targeted and/or antibody-depleted donor or recipient mice, we have shown that this effect depends on CD1d recognition and requires the additional involvement of both NK and CD8+ T cells. Interferon-gamma production by both NK T cells and downstream, non-NK T cells, is essential for protection, and perforin production by effector cells, but not NK T cells, is also critical. The protective mechanisms in this more physiologically relevant system are distinct from those associated with alpha-GalCer-induced, NK T cell-mediated, tumor rejection. This study demonstrates that, in addition to their importance in tumor immunotherapy induced by IL-12 or alpha-GalCer, NK T cells can play a critical role in tumor immunosurveillance, at least against MCA-induced sarcomas, in the absence of exogenous stimulation.
Crowe
Nadine Y
NY
Department of Pathology and Immunology, Monash University Medical School, Melbourne, Victoria 3181, Australia.
Smyth
Mark J
MJ
Godfrey
Dale I
DI
D000818:Animals; D018949:Antigens, CD1 / Q000235:genetics / Q000276:immunology; D055610:Antigens, CD1d; D002273:Carcinogens; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D005354:Fibrosarcoma / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D005699:Galactosylceramides / Q000276:immunology; D018390:Gene Targeting; D007157:Immunologic Surveillance / Q000276:immunology*; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D008099:Liver / Q000166:cytology / Q000276:immunology; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology; D008748:Methylcholanthrene; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D011948:Receptors, Antigen, T-Cell / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D012513:Sarcoma, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D014407:Tumor Cells, Cultured
D018949:Antigens, CD1; D055610:Antigens, CD1d; D002273:Carcinogens; D005699:Galactosylceramides; D011948:Receptors, Antigen, T-Cell; D008748:Methylcholanthrene; D007371:Interferon-gamma