Depletion of IL-10- and TGF-beta-producing regulatory gamma delta T cells by administering a daunomycin-conjugated specific monoclonal antibody in early tumor lesions augments the activity of CTLs and NK cells.
It has been demonstrated that gamma delta T cells accumulating in early tumor lesions and those purified from spleen cells of tumor-bearing mice attenuate the activity of CTLs and NK cells. We, therefore, investigated whether depletion of gamma delta T cells from early lesions of tumors results in restoration of CTL and NK cell activities and subsequent regression of tumors. A daunomycin-conjugated anti-gamma delta TCR mAb UC7-13D5 (Dau-UC7) was prepared to efficiently deplete gamma delta T cells. An in vitro study revealed that Dau-UC7 specifically lysed gamma delta TCR+ cells and effectively inhibited splenic gamma delta T cells from tumor-bearing mice to produce cytotoxic cell-suppressive factors. Furthermore, intralesional injections of Dau-UC7 at an early stage of tumor development led to augmentation of tumor-specific CTL as well as NK cell activities and to the resultant regression or growth inhibition of the tumors. On analysis of cytokine profile, gamma delta T cells transcribed mRNAs for IL-10 and TGF-beta, but not IL-4 or IFN-gamma, suggesting the T regulatory 1-like phenotype. Finally, a blocking study with mAbs showed that the inhibitory action of gamma delta T cells on CTLs and NK cells was at least partly mediated by IL-10 and TGF-beta. These results clearly demonstrated the novel mechanism by which T regulatory 1-like gamma delta T cells suppress anti-tumor CTL and NK activities by their regulatory cytokines in early tumor formation.
Seo
N
N
Department of Tumor Biology, Institute of Medical Science, University of Tokyo, Minatoku, Tokyo, Japan. seo445@hama-med.ac.jp
Tokura
Y
Y
Takigawa
M
M
Egawa
K
K
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000918:Antibody Specificity; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology*; D003630:Daunorubicin / Q000494:pharmacology*; D016753:Interleukin-10 / Q000096:biosynthesis*; D007694:Killer Cells, Natural / Q000276:immunology*; D008212:Lymphocyte Depletion; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D013491:Suppressor Factors, Immunologic / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D016207:Cytokines; D016692:Receptors, Antigen, T-Cell, gamma-delta; D013491:Suppressor Factors, Immunologic; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D003630:Daunorubicin