Functionally distinct subsets of human NK cells and monocyte/DC-like cells identified by coexpression of CD56, CD7, and CD4.
ABSTRACT The lack of natural killer (NK) cell-specific markers, as well as the overlap among several common surface antigens and functional properties, has obscured the delineation between NK cells and dendritic cells. Here, novel subsets of peripheral blood CD3/14/19(neg) NK cells and monocyte/dendritic cell (DC)-like cells were identified on the basis of CD7 and CD4 expression. Coexpression of CD7 and CD56 differentiates NK cells from CD56+ monocyte/DC-like cells, which lack CD7. In contrast to CD7+CD56+ NK cells, CD7(neg)CD56+ cells lack expression of NK cell-associated markers, but share commonalities in their expression of various monocyte/DC-associated markers. Using CD7, we observed approximately 60% of CD4+CD56+ cells were CD7(neg) cells, indicating the actual frequency of activated CD4+ NK cells is much lower in the blood than previously recognized. Functionally, only CD7+ NK cells secrete gamma interferon (IFNgamma) and degranulate after interleukin-12 (IL-12) plus IL-18 or K562 target cell stimulation. Furthermore, using CD7 to separate CD56+ NK cells and CD56+ myeloid cells, we demonstrate that unlike resting CD7+CD56+ NK cells, the CD7(neg)CD56+ myeloid cells stimulate a potent allogeneic response. Our data indicate that CD7 and CD56 coexpression discriminates NK cells from CD7(neg)CD56+ monocyte/DC-like cells, thereby improving our ability to study the intricacies of NK-cell subset phenotypes and functions in vivo.
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ABSTRACT: The interferon (IFN)-gamma-induced TRAIL effector mechanism is a vital component of cancer immunosurveillance by natural killer (NK) cells in mice. Here we show that the main source of IFN-gamma is not the conventional NK cell but a subset of B220(+)Ly6C(-) dendritic cells, which are atypical insofar as they express NK cell-surface molecules. Upon contact with a variety of tumor cells that are poorly recognized by NK cells, B220(+)NK1.1(+) dendritic cells secrete high levels of IFN-gamma and mediate TRAIL-dependent lysis of tumor cells. Adoptive transfer of these IFN-producing killer dendritic cells (IKDCs) into tumor-bearing Rag2(-/-)Il2rg(-/-) mice prevented tumor outgrowth, whereas transfer of conventional NK cells did not. In conclusion, we identified IKDCs as pivotal sensors and effectors of the innate antitumor immune response.Nature Medicine 03/2006; 12(2):214-9. · 22.46 Impact Factor
Article: Interferon-producing killer dendritic cells provide a link between innate and adaptive immunity.[show abstract] [hide abstract]
ABSTRACT: Natural killer (NK) cells and dendritic cells (DCs) are, respectively, central components of innate and adaptive immune responses. We describe here a third DC lineage, termed interferon-producing killer DCs (IKDCs), distinct from conventional DCs and plasmacytoid DCs and with the molecular expression profile of both NK cells and DCs. They produce substantial amounts of type I interferons (IFN) and interleukin (IL)-12 or IFN-gamma, depending on activation stimuli. Upon stimulation with CpG oligodeoxynucleotides, ligands for Toll-like receptor (TLR)-9, IKDCs kill typical NK target cells using NK-activating receptors. Their cytolytic capacity subsequently diminishes, associated with the loss of NKG2D receptor (also known as Klrk1) and its adaptors, Dap10 and Dap12. As cytotoxicity is lost, DC-like antigen-presenting activity is gained, associated with upregulation of surface major histocompatibility complex class II (MHC II) and costimulatory molecules, which formally distinguish them from classical NK cells. In vivo, splenic IKDCs preferentially show NK function and, upon systemic infection, migrate to lymph nodes, where they primarily show antigen-presenting cell activity. By virtue of their capacity to kill target cells, followed by antigen presentation, IKDCs provide a link between innate and adaptive immunity.Nature Medicine 03/2006; 12(2):207-13. · 22.46 Impact Factor
Article: NKp46 and NKG2D receptor expression in NK cells with CD56dim and CD56bright phenotype: regulation by histamine and reactive oxygen species.[show abstract] [hide abstract]
ABSTRACT: The cytotoxicity of natural killer (NK) cells is dependent on the interaction between target cell ligands and a series of stimulatory receptors on NK cells. Two of these triggering receptors, the NKp46 natural cytotoxicity receptor (NKp46) and the major histocompatibility complex (MHC) class I-interactive NKG2D receptor, are deficiently expressed by NK cells recovered from patients with acute myeloid leukaemia (AML), but little is known regarding the regulation of NKp46 and NKG2D expression. Here we report that mononuclear and polymorphonuclear phagocytes downregulate the cell surface density of NKp46 and NKG2D on NK cells with CD56(dim) phenotype in vitro by a mechanism that is dependent on the availability of phagocyte-derived reactive oxygen species (ROS). Histamine maintained NKp46 and NKG2D expression despite the presence of inhibitory phagocytes by targeting an H2 receptor on phagocytes. By contrast, NKp46 and NKG2D expression by the CD56(bright) subset of NK cells was resistant to inhibition by phagocytes. Our findings are suggestive of a novel mechanism of relevance to the regulation of NKp46/NKG2D receptor expression. Moreover, our findings suggest that the previously reported action of histamine on NK cell-mediated killing of leukaemic cells may be related to the preservation of activatory NK-cell receptors.British Journal of Haematology 02/2006; 132(1):91-8. · 4.94 Impact Factor