A Novel KIR-associated Function: Evidence That CpG DNA Uptake and Shuttling to Early Endosomes is Mediated by KIR3DL2

Human natural killer (NK) cells express Toll-like receptor 9 (TLR9) transcript and, upon exposure to microbial CpG oligodeoxynucleotide (ODN), release cytokines and kill target cells. Here we show that NK cell treatment with CpG ODN results in down-modulation of KIR3DL2 inhibitory receptor from the cell surface and in its cointernalization with CpG ODN. CpG ODN-induced interferon-γ (IFN-γ) release is mostly confined to KIR3DL2(+) NK cells, thus suggesting a crucial role of KIR3DL2 in CpG ODN-mediated NK responses. Using soluble receptor molecules, we demonstrate the direct binding of KIR3DL2 to ODNs and we show that the D0 domain is involved primarily in this interaction. KIR3DL2 modulation is also induced in malignant cells of Sézary cutaneous T-cell lymphoma, a disease in which KIR3DL2 represents a typical marker of malignant T cells. Confocal microscopy analysis suggests that, in human NK cells, CpG ODN can encounter TLR9 in early endosomes after being shuttled to these sites by KIR3DL2, which functions as a CpG ODN receptor at the cell surface. This novel KIR-associated function emphasizes the antimicrobial role of NK cells in the course of infection.