Previous studies have shown that TGF-β acts cooperatively with IL-6 to elicit a high frequency of IL-17-secreting CD4(+) T cells (termed Th17) and an elevated CD8(+)IL-17(+) T cell population (termed Tc17). These CD8(+) cells fail to behave like most cytotoxic T lymphocytes that express IFN-γ and granzyme B, but they exhibit a noncytotoxic phenotype. Although a significant increase in the number of these Tc17 cells was found in tumors, their role and interaction with other cell types remain unclear. In this study, we demonstrate that the presence of CD4(+)CD25(-) T cells, but not the CD4(+)CD25(+) (regulatory T [Treg]) cell population, significantly reduced the elicitation of Tc17 cells, possibly as a result of the induction of apoptotic signals. Importantly, these signals may be derived from soluble mediators, and the addition of anti-IL-2 restored the reduction of Tc17 cells in the presence of CD4(+)CD25(-) T cells. Finally, the elicited Tc17 and Treg cells exhibited a close association in patients with head and neck cancer, indicating that the surrounding Treg cells might maintain the survival of the Tc17 cells. Taken together, these results reveal an intriguing mechanism in which Tc17 cells are controlled by a finely tuned collaboration between the different types of CD4(+) T cells in distinct tumor microenvironments.