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NK cells express different TLRs, such as TLR3, TLR7, and TLR9, but little is known about their role in NK cell stimulation. In this study, we used specific agonists (poly (I: C), loxoribine, and synthetic oligonucleotides containing unmethylated CpG sequences to stimulate human NK cells without or with suboptimal doses of IL-12, IL-15, or IFN-α, and investigated the secretion of IFN-γ, cytotoxicity, and expression of the activating receptor NKG2D. Poly (I: C) and loxoribine, in conjunction with IL-12, but not IL-15, triggered secretion of IFN-γ. Inhibition of IFN-γ secretion by chloroquine suggested that internalization of the TLR agonists was necessary. Also, secretion of IFN-γ was dependent on MEK1/ERK, p38 MAPK, p70 S6 kinase, and NF-κB, but not on calcineurin. IFN-α induced a similar effect, but promoted lesser IFN-γ secretion. However, cytotoxicity (51 Cr release assays) against MHC class I-chain related A (MICA …