Depletion of IL-10- and TGF-β-Producing Regulatory γδ T Cells by Administering a Daunomycin-Conjugated Specific Monoclonal Antibody in Early Tumor Lesions Augments the Activity of CTLs and NK Cells

Abstract

AbstractIt has been demonstrated that γδ 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 γδ 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-γδTCR mAb UC7-13D5 (Dau-UC7) was prepared to efficiently deplete γδ T cells. An in vitro study revealed that Dau-UC7 specifically lysed γδTCR+ cells and effectively inhibited splenic γδ 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, γδ T cells transcribed mRNAs for IL-10 and TGF-β, but not IL-4 or IFN-γ, suggesting the T regulatory 1-like phenotype. Finally, a blocking study with mAbs showed that the inhibitory action of γδ T cells on CTLs and NK cells was at least partly mediated by IL-10 and TGF-β. These results clearly demonstrated the novel mechanism by which T regulatory 1-like γδ T cells suppress anti-tumor CTL and NK activities by their regulatory cytokines in early tumor formation.