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Abstract Osteoclasts (OCs) and much less dendritic cells (DCs) induce significant expansion and functional activation of NK cells, and furthermore, the OC-expanded NK cells preferentially increase the expansion and activation of CD8+ T cells by targeting CD4+ T cells. When autologous OCs were used to expand patient NK cells much lower percentages of expanded CD8+ T cells, decreased numbers of expanded NK cells and decreased functions of NK cells could be observed, and the addition of allogeneic healthy OCs increased the patients’ NK function. Mechanistically, OC-expanded NK cells were found to lyse CD4+ T cells but not CD8+ T cells suggesting potential selection of CD8+ T cells before their expansion by OC activated NK cells. In agreement, Increased IFN-γ secretion, and NK cell-mediated cytotoxicity and higher percentages of CD8+ T cells, in various tissue compartments of oral tumor-bearing hu-BLT mice in response to immunotherapy by OC-expanded NK cells were observed. Thus, our results indicate an important relationship between NK and CD8+ T cells.