Recruitment and Activation of Natural Killer (Nk) Cells in Vivo Determined by the Target Cell Phenotype

Glas, Rickard; Franksson, Lars; Une, Clas; Eloranta, Maija‐Leena; Öhlén, Claes; Örn, Anders; Kärre, Klas

doi:10.1084/jem.191.1.129

Cited by 138 publications

(110 citation statements)

References 63 publications

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“…A problem with this interpretation is that it examined only spontaneous NK cell cytolytic activity. Recent studies have shown that the NK cell population in mature mice is nearly devoid of cytolytic activity until activated by stimuli (priming) such as poly(I:C), viral infection, or target cells that express ligands such as Rae1 that stimulate NK cells (40,41). NK cells with spontaneous cytolytic activity are therefore likely to represent only a small subset of the total NK1.1 ϩ CD3 Ϫ population in normal untreated mice.…”

Section: Discussionmentioning

confidence: 99%

Turnover and Proliferation of NK Cells in Steady State and Lymphopenic Conditions

Jamieson

Isnard

Dorfman

et al. 2004

The Journal of Immunology

149

122

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To gain insight into NK cell dynamics, we investigated the turnover and proliferation rates of NK cells in normal and lymphopenic conditions. In contrast to previous reports suggesting a very rapid turnover of NK cells, continuous 5-bromo-2′-deoxyuridine (BrdU)-labeling studies demonstrated that the time necessary for labeling 50% of splenic NK cells in mature mice was 17 days, similar to the rate of labeling of memory T cells. In contrast, in young mice, splenic NK cells labeled very rapidly with BrdU, although cell cycle analyses and BrdU pulse-labeling studies suggested that most of this proliferation occurred in a precursor population. A somewhat larger percentage of bone marrow NK cells was cycling, suggesting that these proliferating cells are the precursors of the mostly nondividing or slowly dividing splenic NK cells. Splenic NK cells from mature mice also did not proliferate significantly when transferred to normal mice, but did proliferate when transferred to irradiated mice. Thus, NK cells, like T cells, undergo homeostatic proliferation in a lymphopenic environment. Homeostatic proliferation of NK cells was not dependent on host cell class I molecules or host production of IL-15. Nevertheless, the number of recovered NK cells was much lower in IL-15−/− hosts. These results suggest that IL-15 is not essential for homeostatic proliferation of NK cells, but is necessary for survival of the NK cells. Our results provide important basic information concerning the production and replacement of NK cells.

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Section: Discussionmentioning

confidence: 99%

Turnover and Proliferation of NK Cells in Steady State and Lymphopenic Conditions

Jamieson

Isnard

Dorfman

et al. 2004

The Journal of Immunology

149

122

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“…In this study, we explored how NK cells were recruited to a nonlymphoid tissue, with the peritoneal cavity as a model. Studies looking at NK-cell recruitment to this area have been conducted previously, but migration was in those experiments induced by inoculation of tumors or infectious agents [13][14][15]. In the case of tumor inoculation i.p., recruitment was shown to be dependent on TNF [14].…”

Section: Discussionmentioning

confidence: 99%

“…NK cells are found in both nonlymphoid and lymphoid tissues including lung, liver, blood, spleen, and LN [9]. Several studies have demonstrated that NK cells migrate to different tissues in response to stimuli, such as allergic responses, infections, or tumor growth [10][11][12][13][14][15][16][17][18][19]. Four chemokine receptors, CCR2, CCR5, CXCR3 and CX3CR1, have been shown to be particularly important for mouse NK-cell migration to various inflammatory stimulus [4,9].…”

Section: Introductionmentioning

confidence: 99%

Plasmacytoid dendritic cell‐induced migration and activation of NK cells in vivo

Persson

Chambers

2010

Eur J Immunol

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NK cells are cytotoxic cells of the innate immune system. They have been found to be critical in the defense against infections and also against some tumors. Recent studies have shown that NK cells require signals from accessory cells to induce their recruitment and activation at the site of infection or tumor growth. In this study, we examined whether plasmacytoid DC (pDC) could recruit and activate NK cells in vivo. When CpG-stimulated pDC were injected i.p. to C57BL/6 mice, they efficiently recruited NK cells, a process that was dependent on NK cell CXCR3 and CD62L and in part on CCR5. NK cells isolated from the peritoneum of mice inoculated with TLR7/8 or TLR9-stimulated pDC exhibited greater cytotoxicity against YAC-1 tumor cells than NK cells recovered from mice inoculated with control pDC. The present results are discussed in relation to pDC-induced NK cell migration and activation in vivo.Key words: Cellular activation . Cell migration . Costimulatory moleculers . Dendritic cells . NK cell IntroductionNK cells are lymphocytes of the innate immune system that play a crucial role in the early host defense against infections and some tumors [1]. NK cells have potent cytotoxic functions and are efficient producers of several cytokines including IFN-g, TNF-a, and GM-CSF [2]. The latter contribute to the immunoregulatory properties of NK cells, which affect anti-microbial and anti-tumor responses as well as the outcome of many autoimmune and hypersensitivity reactions [3]. By their cytotoxicity and cytokine production, NK cells can affect CTL responses in infection and tumor models as well as B-cell responses [4][5][6][7][8]. NK cells are found in both nonlymphoid and lymphoid tissues including lung, liver, blood, spleen, and LN [9]. Several studies have demonstrated that NK cells migrate to different tissues in response to stimuli, such as allergic responses, infections, or tumor growth [10][11][12][13][14][15][16][17][18][19]. Four chemokine receptors, CCR2, CCR5, CXCR3 and CX3CR1, have been shown to be particularly important for mouse NK-cell migration to various inflammatory stimulus [4,9]. However, other molecules such as CD62L, IFN-g, sphingosine 1-phosphate receptor, and TNF-a are also important for the NKcell migration in mice. For example, blocking CD62L with Ab prevents the egress of NK cells from blood into LN [4]. IFN-g modulates migration by inducing the production of CXCL10 (IP10) [20]. Thus, mice deficient in IFN-g also exhibit reduced CXCL10 production. In mice lacking sphingosine 1-phosphate receptor, NK cells accumulate in the LN and bone marrow while being absent from blood, spleen, or lungs [21]. Thus chemokine activation of NK cells is important for their recruitment to inflammatory sites. In both mice and humans, two main types of ''DC'' exist, conventional DC (cDC), including both lymphoid tissue-resident DC and migratory DC, and so-called plasmacytoid DC (pDC). In mice, cDC in the spleen can be further subdivided into the CD8a 1 and CD8a À populations. The former are involved in crosspr...

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“…Inhibitory receptors interacting with MHC selfmolecules interfere with positive signaling, thus protecting normal tissue from NK-cell attack. As predicted by the ''missing self hypothesis'', interaction of NK cells with target cells expressing reduced levels of self MHC, such as virus-infected or tumor cells, ignites the lytic machinery [3][4][5][6]. Inhibitory receptors of mouse NK cells comprise several Ly49 receptors, CD94/NKG2A [7] or CD48 [8].…”

Section: Introductionmentioning

confidence: 99%

Requirements for control of B‐cell lymphoma by NK cells

et al. 2010

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The role of NK cells in the control of endogenously arising tumors is still unclear. We monitored activation and effector functions of NK cells in a c‐myc‐transgenic mouse model of spontaneously arising lymphoma. At early stages, tumors demonstrated reduced MHC class I expression and increased expression of natural killer group 2D ligands (NKG2D‐L). NK cells in these tumors showed an activated phenotype that correlated with the loss of tumor MHC class I. With increasing tumor load however, NK‐cell effector functions became progressively paralyzed or exhausted. In later stages of disease, tumors re‐expressed MHC class I and lost NKG2D‐L, suggesting a role of these two signals for NK cell‐mediated tumor control. Testing a panel of lymphoma cell lines expressing various MHC class I and NKG2D‐L levels suggested that NK cell‐dependent tumor control required a priming and a triggering signal that were provided by MHC class I down‐regulation and by NKG2D‐L, respectively. Deleting either of the “two signals” resulted in tumor escape. At early disease stages, immune stimulation through TLR‐ligands in vivo efficiently delayed lymphoma growth in a strictly NK cell‐dependent manner. Thus, NK‐receptor coengagement is crucial for NK‐cell functions in vivo and especially for NK cell‐mediated tumor surveillance.

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Recruitment and Activation of Natural Killer (Nk) Cells in Vivo Determined by the Target Cell Phenotype

Cited by 138 publications

References 63 publications

Turnover and Proliferation of NK Cells in Steady State and Lymphopenic Conditions

Turnover and Proliferation of NK Cells in Steady State and Lymphopenic Conditions

Plasmacytoid dendritic cell‐induced migration and activation of NK cells in vivo

Requirements for control of B‐cell lymphoma by NK cells

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