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 tum or lesions and those purified from spleen cells of tumor-bearing mice atten uate the activity of CTLs and NK cells. We, therefore, investigated whether depletion of ya T cells from early lesions of tumors results in restoratio n of CTL and NK cell activities and subsequent regression of tumors. A daun omycin-conjugated anti-gamma delta TCR mAb UC7-13D5 (Dau-UC7) was prepared to efficiently deplete ya 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-supp ressive factors. Furthermore, intralesional injections of Dau-UC7 at an ear ly stage of tumor development led to augmentation of tumor-specific CTL as well as NK cell activities and to the resultant regression or growth inhibi tion of the tumors. On analysis of cytokine profile, gamma delta T cells tr anscribed mRNAs for IL-10 and TGF-P, but not IL-4 or IFN-gamma, suggesting the T regulatory 1-like phenotype. Finally, a blocking study with mAbs show ed that the inhibitory action of ya T cells on CTLs and NK cells was at lea st partly mediated by IL-10 and TGF-beta, These results clearly demonstrate d the novel mechanism by which T regulatory 1-like gamma delta T cells supp ress anti-tumor CTL and NK activities by their regulatory cytokines in earl y tumor formation.