A critical role for natural killer T cells in immunosurveillance of methylcholanthrene-induced sarcomas

J Exp Med. 2002 Jul 1;196(1):119-27. doi: 10.1084/jem.20020092.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD1 / genetics
  • Antigens, CD1 / immunology
  • Antigens, CD1d
  • Carcinogens
  • Cell Division / immunology
  • Cells, Cultured
  • Dose-Response Relationship, Immunologic
  • Fibrosarcoma / chemically induced
  • Fibrosarcoma / immunology*
  • Fibrosarcoma / pathology
  • Galactosylceramides / immunology
  • Gene Targeting
  • Immunologic Surveillance / immunology*
  • Immunotherapy, Adoptive / methods*
  • Interferon-gamma / deficiency
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Killer Cells, Natural / transplantation
  • Liver / cytology
  • Liver / immunology
  • Lymphocytes / cytology
  • Lymphocytes / immunology
  • Methylcholanthrene
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasm Transplantation
  • Receptors, Antigen, T-Cell / deficiency
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Sarcoma, Experimental / chemically induced
  • Sarcoma, Experimental / immunology*
  • Sarcoma, Experimental / pathology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / transplantation
  • Tumor Cells, Cultured

Substances

  • Antigens, CD1
  • Antigens, CD1d
  • Carcinogens
  • Galactosylceramides
  • Receptors, Antigen, T-Cell
  • Methylcholanthrene
  • Interferon-gamma