NK cells represent innate effectors and protect the host against foreign invaders such as viruses, parasites, bacteria, or transformed cells 6. Following stimulation, NK cells release large amounts of immunostimulatory cytokines including IFN-γ and TNF-α, and trigger target cell death through the perforin/granzyme pathway or extrinsic pathways
of apoptosis (Fas/FasLigand or TRAIL) 7. Expression of activating or inhibitory receptors on NK cells enables self and RO4929097 molecular weight non-self recognition 8. The NK group family receptor (e.g. NKG2D), the killer cell immunoglobulin-like receptors (KIR, e.g. CD158a and CD158b) and the natural cytotoxicity receptors (e.g. NKp44) coordinate recognition and killing of target cells while avoiding the destruction of autologous healthy tissues 9. Depending on the balance between inhibitory and activating signals engaged by ligands expressed on tumor cells, NK cells are triggered to kill or to ignore target cells. For example, NKG2D interacts
with its ligands major histocompatibility complex (MHC) class I-related chains (MICs) A and B (MICA and MICB), contributing to the control of epithelial tumors. In cancer selleck chemical patients, NK cell activation can be hampered by tumor-mediated shedding of MICs 10. Recently, it has been reported that nTreg cells suppress NK cell effector functions in vitro and in vivo 11, 12. Ghiringhelli et al. have shown that Treg cell-derived TGF-β inhibits NK cell cytolytic activity and downregulates NKG2D but does not inhibit the production of IFN-γ by NK cells stimulated by IL-2Rγ-chain-dependent cytokines
11. Surprisingly, the studies focusing on the interaction of iTreg cells and Atorvastatin NK cells are not available, so far. In this study, we determined how tumor iTreg cells modulate NK cell function. We provide evidence that in a human in vitro system iTreg cells promote perforin and FasL-dependent cytotoxicity of non-activated NK cells, while IL-2-mediated NK cell activation was inhibited in the presence of iTreg cells. Our data provide new insights into the complex regulation of human NK cells in the tumor microenvironment. iTreg cells used here have been generated according to a protocol described earlier 13 and showed a purity of >99%. They are known to express the inhibitory cytokines IL-10 and TGF-β at high levels, but — in contrast to nTreg cells — they do not express CD25 (IL-2Rα). This phenotype is found in iTreg cells/Tr1 cells of patients with cancer or autoimmune diseases 4, 14–16 (Fig. 1A). Thus, the iTreg cells generated here — in an in vitro model mimicking the tumor microenvironment — displayed typical iTreg cell-/Tr1 cell properties. As shown in Fig. 1B, iTreg cells inhibited the proliferation of activated CD4+ T cells (from 100 to 8%) significantly.
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