Liver NK1.1+ CD4+ alpha beta T cells activated by IL-12 as a major effector in inhibition of experimental tumor metastasis.
We demonstrate herein evidence that IL-12-activated alpha beta T cells with intermediate TCR (NK1+ TCRint cells) in the liver inhibit metastases in the lung as well as in the liver metastases of i-v. injected tumors. IL-12 administration enhanced NK1 expression of NK1+ TCRint cells (NK1high) and increased CD4 weakly positive (CD4low) TCRint cells, while both CD4+ TCRint cells and double-negative TCRint cells were proportionally diminished. Accordingly, the major parts of NK1high TCRint cells are CD4low cells, and most of these cells are V beta 8+ cells. The cytotoxic assays of IL-12-stimulated hepatic mononuclear cells after treatment with respective Abs and complement in vitro and after sorting revealed that CD4low NK1high TCRint cells are cytotoxic effectors. When IL-12-stimulated hepatic mononuclear cells (but not splenocytes) were transferred into tumor-preinjected mice, EL-4 cell metastases in the liver as well as 3LL cell metastases in the lung were inhibited. The antimetastasis of hepatic mononuclear cells transfer was abrogated by the depletion of NK1+ cells, CD3+ cells, or CD4+ cells but not CD8+ cells before transfer. Moreover, transfer of these cells of nude mice into tumor-preinjected mice also inhibited metastases in both organs. Although NK1+ TCRint cells are nearly absent in the hepatic vein blood, a significant proportion of NK1high TCRint cells appeared by IL-12 administration. These results demonstrate that IL-12-stimulated liver NK1high TCRint cells, including extrathymic ones, are major effectors against tumor metastasis and suggest that the cells migrate and inhibit lung metastases.
Takeda
K
K
Department of Microbiology, Tohoku University School of Dentistry, Sendai, Japan.
Seki
S
S
Ogasawara
K
K
Anzai
R
R
Hashimoto
W
W
Sugiura
K
K
Takahashi
M
M
Satoh
M
M
Kumagai
K
K
D000818:Animals; D000941:Antigens / Q000276:immunology*; D000950:Antigens, Ly; D000954:Antigens, Surface; D015496:CD4-Positive T-Lymphocytes / Q000145:classification / Q000187:drug effects* / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006503:Hepatic Veins / Q000276:immunology; D016219:Immunotherapy, Adoptive; D018664:Interleukin-12 / Q000008:administration & dosage / Q000627:therapeutic use*; D037181:Lectins, C-Type; D008099:Liver / Q000276:immunology*; D008114:Liver Neoplasms, Experimental / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary*; D016031:Liver Transplantation; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D008213:Lymphocyte Activation; D016399:Lymphoma, T-Cell / Q000276:immunology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000941:Antigens; D000950:Antigens, Ly; D000954:Antigens, Surface; C527211:Klrb1c protein, mouse; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018664:Interleukin-12