NK cells activated by Interleukin-4 in cooperation with Interleukin-15 exhibit distinctive characteristics (original) (raw)
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Regulation of mouse NK cell development and function by cytokines
Front Immunol, 2013
Natural Killer (NK) cells are innate lymphocytes with an important role in the early defense against intracellular pathogens and against tumors. Like other immune cells, almost every aspects of their biology are regulated by cytokines. Interleukin (IL)-15 is pivotal for their development, homeostasis, and activation. Moreover, numerous other activating or inhibitory cytokines such as IL-2, IL-4, IL-7, IL-10, IL-12, IL-18, IL-21, Transforming growth factor-β (TGFβ) and type I interferons regulate their activation and their effector functions at different stages of the immune response. In this review we summarize the current understanding on the effect of these different cytokines on NK cell development, homeostasis, and functions during steady-state or upon infection by different pathogens. We try to delineate the cellular sources of these cytokines, the intracellular pathways they trigger and the transcription factors they regulate. We describe the known synergies or antagonisms between different cytokines and highlight outstanding questions in this field of investigation. Finally, we discuss how a better knowledge of cytokine action on NK cells could help improve strategies to manipulate NK cells in different clinical situations.
IL-2 mediates NK cell proliferation but not hyperactivity
Immunologic research, 2017
Natural killer cells play a major role in innate immunity against tumor and virus-infected cells. NK cells express activating and inhibitory receptors to regulate their function. It has been established that modulation in the NK cell receptor profile results in altered function of NK cell against target cells. Here, we study the effect of IL-2 stimulation on NK cell inhibitory receptors Ly49A, Ly49C, and activating receptor Ly49D in C57BL/6 mice. It was observed that there was significant increase in expression of Ly49A but no change in expression of Ly49C and Ly49D on IL-2 stimulation. We further noticed that although IL-2 stimulation increased the NK cell population and expression of activation marker NK1.1 but IL-2 stimulation does not cause hyper-responsiveness in NK cells, as there was no increase in MIP-1α and IFN-γ production in IL-2 stimulated NK cells as compared to unstimulated controls. These findings provide a framework to understand the effect of IL-2 stimulation on cog...
European Journal of Immunology, 1992
Natural killer (NK) cells can be differentiated into lymphokine-activated killer (LAK) effectors following stimulation with interleukin (1L)-2. This induction can be negatively regulated by IL-4. In this study,we demonstrate that the stimulation of NK cells through the CD2 pathway with (9-1 + 9.6) monoclonal antibodies can also induce these cells to secrete tumor necrosis factor-a (TNF-a) and to differentiate into LAK effectors. More importantly, our data indicate that, in contrast to the IL-Zinduced LAK generation, the anti-CD2-triggered LAK activity was not regulated by IL-4. IL-4 was found to enhance the LAK activity as well as NK cell proliferation following activation with anti-CD2 by a mechanism involving, at least in part, an increased TNF-a production. Using immobilized monoclonal antibodies against the Fc receptor (FcyRIII or CD16) for NK stimulation, we also observed that the anti-CD16-induced LAK activity was not inhibited by IL-4. These data further point to a pivotal role of TKF-a as a regulatory cytokine in anti-CD2-induced LAK generation, and suggest that IL-4 could serve as a discriminatory factor between two distinct pathways involved in the activation of non-MHC-restricted cytotoxicity.
Immunology, 2008
CD1d-restricted natural killer T (NKT) cells can rapidly produce T helper type 1 (Th1) and Th2 cytokines and also play regulatory or pathological roles in immune responses. NKT cells are able to expand when cultured with a-galactosylceramide (a-GalCer) and interleukin (IL)-2 in a CD1drestricted manner. However, the expansion ratio of human NKT cells is variable from sample to sample. In this study, we sought to determine what factor or factors are responsible for efficient in vitro expansion of NKT cells from various inbred mouse strains. Although the proportion of NKT cells in the spleen was nearly identical in each mouse strain, the growth rates of NKT cells cultured in vitro with a-GalCer and IL-2 were highly variable. NKT cells from the B6C3F1 and BDF1 mouse strains expanded more than 20-fold after 4 days in culture. In contrast, NKT cells from the strain C3H/HeN did not proliferate at all. We found that cell expansion efficiency correlated with the level of IL-4 detectable in the supernatant after culture. Furthermore, we found that exogenous IL-4 augmented NKT cell proliferation early in the culture period, whereas interferon (IFN)-c tended to inhibit NKT cell proliferation. Thus, the ratio of production of IL-4 and IFN-c was important for NKT cell expansion but the absolute levels of these cytokines did not affect expansion. This finding suggests that effective expansion of NKT cells requires Th2-biased culture conditions.
The Journal of Immunology, 2005
In the course of inflammatory responses in peripheral tissues, NK cells may be exposed to cytokines such as IL-12 and IL-4 released by other cell types that may influence their functional activities. In the present study we comparatively analyzed purified human peripheral blood NK cells that had been exposed to either IL-12 or IL-4 during short (overnight) incubation. We show that although IL-12-cultured NK cells produced abundant IFN-␥, TNF-␣, and GM-CSF in response to stimuli acting on the NKp46activating receptor, IL-4-cultured NK cells did not release detectable levels of these cytokines. In contrast, IL-4-cultured NK cells produced significant levels of TNF-␣ and GM-CSF only when stimulated with PMA and ionomycin. In no instance could the production of IL-5 and IL-13 be detected. Importantly, IL-12-cultured, but not IL-4-cultured, NK cells displayed strong cytolytic activity against various tumor cells or immature dendritic cells (DCs). Moreover, only NK cells that had been cultured in IL-12 were able to induce substantial DC maturation. Our data suggest that NK cells exposed to IL-12 for a time interval compatible with in vivo responses may favor the selection of appropriate mature DCs for subsequent Th1 cell priming in secondary lymphoid organs. On the contrary, NK cells exposed to IL-4 do not exert DC selection, may impair efficient Th1 priming, and favor either tolerogenic or Th2-type responses.
The Journal of Immunology, 2001
IL-2 and IL-15 are lymphocyte growth factors produced by different cell types with overlapping functions in immune responses. Both cytokines costimulate lymphocyte proliferation and activation, while IL-15 additionally promotes the development and survival of NK cells, NKT cells, and intraepithelial lymphocytes. We have investigated the effects of IL-2 and IL-15 on proliferation, cytotoxicity, and cytokine secretion by human PBMC subpopulations in vitro. Both cytokines selectively induced the proliferation of NK cells and CD56 ؉ T cells, but not CD56 ؊ lymphocytes. All NK and CD56 ؉ T cell subpopulations tested (CD4 ؉ , CD8 ؉ , CD4 ؊ CD8 ؊ , ␣TCR ؉ , ␥␦TCR ؉ , CD16 ؉ , CD161 ؉ , CD158a ؉ , CD158b ؉ , KIR3DL1 ؉ , and CD94 ؉ ) expanded in response to both cytokines, whereas all CD56 ؊ cell subpopulations did not. Therefore, previously reported IL-15-induced ␥␦ and CD8 ؉ T cell expansions reflect proliferations of NK and CD56 ؉ T cells that most frequently express these phenotypes. IL-15 also expanded CD8␣ ؉  ؊ and V␣24V11 TCR ؉ T cells. Both cytokines stimulated cytotoxicity by NK and CD56 ؉ T cells against K562 targets, but not the production of IFN-␥, TNF-␣, IL-2, or IL-4. However, they augmented cytokine production in response to phorbol ester stimulation or CD3 cross-linking by inducing the proliferation of NK cells and CD56 ؉ T cells that produce these cytokines at greater frequencies than other T cells. These results indicate that IL-2 and IL-15 act at different stages of the immune response by expanding and partially activating NK receptor-positive lymphocytes, but, on their own, do not influence the Th1/Th2 balance of adaptive immune responses.
Cytokine regulation of natural killer cell effector functions
Initially described as effectors of natural cytotoxicity and critical players for the control of viral infections and tumor growth, recent investigations unraveled more widespread functions for the natural killer (NK) cells. Through the establishment of a crosstalk with dendritic cells, NK cells promote T helper-1-and cytotoxic T lymphocyte-mediated immunity, whereas through the establishment of a crosstalk with macrophages, NK cells contribute to the activation of their microbicidal functions. Recent evidence has shown that NK cells also display memory, a characteristic thought to be privative of T and B cells, and that NK cells acquire their mature phenotype during a complex ontogeny program which tunes their activation threshold. Cytokines play critical roles in regulating all aspects of immune responses, including lymphoid development, homeostasis, differentiation, tolerance, and memory. Cytokines such as interleukin (IL)-2, IL-12, IL-15, IL-18, IL-21, and type I interferons constitute pivotal factors involved in the maturation, activation, and survival of NK cells. In addition, the discovery of novel cytokines is increasing the spectrum of soluble mediators that regulate NK cell immunobiology. In this review, we summarize and integrate novel concepts about the role of different cytokines in the regulation of NK cell function. We believe that a full understanding of how NK cells become activated and develop their effector functions in response to cytokines and other stimuli may lead to the development of novel immunotherapeutic strategies for the treatment of different types of cancer, viral infections, and chronic autoimmune diseases.