Mice with a targeted mutation in lymphotoxin-alpha exhibit enhanced tumor growth and metastasis: impaired NK cell development and recruitment.
Mice deficient in lymphotoxin (LT)-alpha lack peripheral lymph nodes and Peyer's patches and have profound defects in development of follicular dendritic cell networks, germinal center formation, and T/B cell segregation in the spleen. Although LTalpha is known to be expressed by NK cells as well as T and B lymphocytes, the requirement of LTalpha for NK cell functions is largely unknown. To address this issue, we have assessed NK cell functions in LTalpha-deficient mice by evaluating tumor models with known requirements for NK cells to control their growth and metastasis. Syngeneic B16F10 melanoma cells inoculated s.c. grew more rapidly in LTalpha-/- mice than in the wild-type littermates, and the formation of experimental pulmonary metastases was significantly enhanced in LTalpha-/- mice. Although LTalpha-/- mice exhibited almost a normal total number of NK cells in spleen, they showed an impaired recruitment of NK cells to lung and liver. Additionally, lytic NK cells were not efficiently produced from LTalpha-/- bone marrow cells in vitro in the presence of IL-2 and IL-15. These data suggest that LTalpha signaling may be involved in the maturation and recruitment of NK cells and may play an important role in antitumor surveillance.
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Laboratory of Molecular Immunoregulation, Division of Basic Sciences, Science Applications International Corp.-Frederick, National Cancer Institute-Frederic Cancer Research and Development Center, MD 21702, USA.
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Shakhov
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Wiltrout
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Nedospasov
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D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D018827:Carcinoma, Lewis Lung; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000276:immunology; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000556:secondary*; D008213:Lymphocyte Activation / Q000235:genetics; D008233:Lymphotoxin-alpha / Q000235:genetics*; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology
D008233:Lymphotoxin-alpha