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      IL-18–induced CD83 + CCR7 + NK helper cells

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          In addition to their cytotoxic activities, natural killer (NK) cells can have immunoregulatory functions. We describe a distinct “helper” differentiation pathway of human CD56 + CD3 NK cells into CD56 + /CD83 + /CCR7 + /CD25 + cells that display high migratory responsiveness to lymph node (LN)–associated chemokines, high ability to produce interferon- γ upon exposure to dendritic cell (DC)- or T helper (Th) cell–related signals, and pronounced abilities to promote interleukin (IL)-12p70 production in DCs and the development of Th1 responses. This helper pathway of NK cell differentiation, which is not associated with any enhancement of cytolytic activity, is induced by IL-18, but not other NK cell–activating factors. It is blocked by prostaglandin (PG)E 2, a factor that induces a similar CD83 + /CCR7 + /CD25 + LN-homing phenotype in maturing DCs. The current data demonstrate independent regulation of the “helper” versus “effector” pathways of NK cell differentiation and novel mechanisms of immunoregulation by IL-18 and PGE 2.

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          Reciprocal Activating Interaction between Natural Killer Cells and Dendritic Cells

          We analyzed the interaction between human peripheral blood natural killer (NK) cells and monocyte-derived immature dendritic cells (DC). Fresh NK cells were activated, as indicated by the induced expression of the CD69 antigen, and their cytolytic activity was strongly augmented by contact with lipopolysaccharide (LPS)-treated mature DC, or with immature DC in the presence of the maturation stimuli LPS, Mycobacterium tuberculosis or interferon (IFN)-α. Reciprocally, fresh NK cells cultured with immature DC in the presence of the maturation stimuli strongly enhanced DC maturation and interleukin (IL)-12 production. IL-2–activated NK cells directly induced maturation of DC and enhanced their ability to stimulate allogeneic naive CD4+ T cells. The effects of NK cells were cell contact dependent, although the secretion of IFN-γ and TNF also contributed to DC maturation. Within peripheral blood lymphocytes the reciprocal activating interaction with DC was restricted to NK cells, because the other lymphocyte subsets were neither induced to express CD69, nor induced to mature in contact with DC. These data demonstrated for the first time a bidirectional cross talk between NK cells and DC, in which NK cells activated by IL-2 or by mature DC induce DC maturation.
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            Human Dendritic Cells Activate Resting Natural Killer (NK) Cells and Are Recognized via the NKp30 Receptor by Activated NK Cells

            During the innate response to many inflammatory and infectious stimuli, dendritic cells (DCs) undergo a differentiation process termed maturation. Mature DCs activate antigen-specific naive T cells. Here we show that both immature and mature DCs activate resting human natural killer (NK) cells. Within 1 wk the NK cells increase two– to fourfold in numbers, start secreting interferon (IFN)-γ, and acquire cytolytic activity against the classical NK target LCL721.221. The DC-activated NK cells then kill immature DCs efficiently, even though the latter express substantial levels of major histocompatibility complex (MHC) class I. Similar results are seen with interleukin (IL)-2–activated NK cell lines and clones, i.e., these NK cells kill and secrete IFN-γ in response to immature DCs. Mature DCs are protected from activated NK lysis, but lysis takes place if the NK inhibitory signal is blocked by a human histocompatibility leukocyte antigen (HLA)-A,B,C–specific antibody. The NK activating signal mainly involves the NKp30 natural cytotoxicity receptor, and not the NKp46 or NKp44 receptor. However, both immature and mature DCs seem to use a NKp30 independent mechanism to act as potent stimulators for resting NK cells. We suggest that DCs are able to control directly the expansion of NK cells and that the lysis of immature DCs can regulate the afferent limb of innate and adaptive immunity.
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              CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link between adaptive and innate immunity.

              Natural killer (NK) cells are innate lymphocytes that provide cytokines critical for early host defense against pathogens. One subset of human NK cells (CD56(bright)) constitutively expresses the high-affinity interleukin 2 (IL-2) receptor and produces immunoregulatory cytokines. Here, we demonstrate that CD56(bright) NK cells are present in human lymph nodes and that endogenous T cell-derived IL-2, acting through the NK high-affinity IL-2 receptor, costimulates CD56(bright) NK cells to secrete IFN-gamma. Thus, adaptive immunoregulators influence innate cytokine production, which in turn may influence the developing antigen-specific immune response. These data show a dynamic interaction between innate and adaptive human lymphocytes and emphasize the importance of studying interactions between immune components to understand the immune response as a whole.

                Author and article information

                J Exp Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                3 October 2005
                : 202
                : 7
                : 941-953
                [1 ]Department of Surgery, University of Pittsburgh
                [2 ]Department of Cell Biology and Physiology, University of Pittsburgh
                [3 ]Department of Radiation Oncology, University of Pittsburgh
                [4 ]Department of Immunology, University of Pittsburgh
                [5 ]Department of Medicine, University of Pittsburgh
                [6 ]Department of Infectious Diseases and Microbiology, University of Pittsburgh
                [7 ]University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213
                Author notes

                CORRESPONDENCE Pawel Kalinski: kalinskip@

                Copyright © 2005, The Rockefeller University Press



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