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Differential IL-18 Dependence of Canonical and Adaptive NK Cells for Antibody Dependent Responses to P. falciparum.

ABSTRACT: Human adaptive natural killer (NK) cells have diminished reliance on accessory cytokines for their activation whilst being efficiently activated by infected host cells in conjunction with pathogen specific antibodies. Here, we show that potent antibody-dependent NK cell responses are induced by Plasmodium falciparum infected erythrocytes (iRBC) in peripheral blood mononuclear cells (PBMC) from malaria-exposed Gambian individuals in the presence of autologous sera, which are absent in those from malaria-naïve UK individuals. However, malaria hyper-immune serum promotes rapid NK cell responses to iRBC in cells from both Gambian and UK individuals. Among Gambians, highly differentiated, adaptive (CD56dimFcεR1γ-CD57+) NK cells dominate both antibody-dependent NK cell IFN-γ responses and degranulation responses, whereas among UK individuals these responses are predominantly found within canonical, highly differentiated CD56dimFcεR1γ+CD57+ NK cells. Indeed, overall frequencies of adaptive, FcεR1γ-CD57+ NK cells are significantly higher among Gambian donors compared to HCMV-infected and HCMV-uninfected UK adults. Among UK individuals, antibody-dependent NK cell IFN-γ responses to iRBC were dependent on IL-18 whereas among Gambians, the predominant adaptive FcεR1γ- NK cell response was IL-18 (and accessory cell) independent (although the lower frequency response of canonical FcεR1γ NK cells did rely on this cytokine).

SUBMITTER: Sherratt S

PROVIDER: S-EPMC7137096 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Synergy between Common ? Chain Family Cytokines and IL-18 Potentiates Innate and Adaptive Pathways of NK Cell Activation.

Project description:Studies to develop cell-based therapies for cancer and other diseases have consistently shown that purified human natural killer (NK) cells secrete cytokines and kill target cells after in vitro culture with high concentrations of cytokines. However, these assays poorly reflect the conditions that are likely to prevail in vivo in the early stages of an infection and have been carried out in a wide variety of experimental systems, which has led to contradictions within the literature. We have conducted a detailed kinetic and dose-response analysis of human NK cell responses to low concentrations of IL-12, IL-15, IL-18, IL-21, and IFN-?, alone and in combination, and their potential to synergize with IL-2. We find that very low concentrations of both innate and adaptive common ? chain cytokines synergize with equally low concentrations of IL-18 to drive rapid and potent NK cell CD25 and IFN-? expression; IL-18 and IL-2 reciprocally sustain CD25 and IL-18R? expression in a positive feedback loop; and IL-18 synergizes with Fc?RIII (CD16) signaling to augment antibody-dependent cellular cytotoxicity. These data indicate that NK cells can be rapidly activated by very low doses of innate cytokines and that the common ? chain cytokines have overlapping but distinct functions in combination with IL-18. Importantly, synergy between multiple signaling pathways leading to rapid NK cell activation at very low cytokine concentrations has been overlooked in prior studies focusing on single cytokines or simple combinations. Moreover, although the precise common ? chain cytokines available during primary and secondary infections may differ, their synergy with both IL-18 and antigen-antibody immune complexes underscores their contribution to NK cell activation during innate and adaptive responses. IL-18 signaling potentiates NK cell effector function during innate and adaptive immune responses by synergy with IL-2, IL-15, and IL-21 and immune complexes.

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Expression data of IL-18 generated murine NK cells

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2012-07-10 | E-GEOD-33627 | biostudies-arrayexpress

An Anti-MICA/B Antibody and IL-15 Rescue Altered NKG2D-Dependent NK Cell Responses in Hepatocellular Carcinoma.

Project description:Natural killer (NK) cells play a pivotal role in cancer immune surveillance, and activating the receptor/ligand interaction may contribute to control the development and evolution of hepatocellular carcinoma (HCC). We investigated the role of the natural killer group 2 member D (NKG2D) activating receptor and its ligand, the major histocompatibility complex class I chain-related protein A and B (MICA/B) in patients with cirrhosis and HCC subjected to surgical resection, patients with cirrhosis and no HCC, and healthy donors (HD). The NKG2D-mediated function was determined in peripheral blood (PB), in tumor-infiltrating lymphocytes (NK-TIL), and in matched surrounding liver tissue (NK-LIL). A group of patients treated with sorafenib because of clinically advanced HCC was also studied. A humanized anti-MICA/B monoclonal antibody (mAb) was used in in vitro experiments to examine NK cell-mediated antibody-dependent cellular cytotoxicity. Serum concentrations of soluble MICA/B were evaluated by ELISA. IL-15 stimulation increased NKG2D-dependent activity which, however, remained dysfunctional in PB NK cells from HCC patients, in line with the reduced NKG2D expression on NK cells. NK-TIL showed a lower degranulation ability than NK-LIL, which was restored by IL-15 stimulation. Moreover, in vitro IL-15 stimulation enhanced degranulation and interferon-γ production by PB NK from patients at month one of treatment with sorafenib. Anti-MICA/B mAb associated with IL-15 was able to induce PB NK cytotoxicity for primary HCC cells in HD and patients with HCC, who also showed NK-TIL degranulation for autologous primary HCC cells. Our findings highlight the key role of the NKG2D-MICA/B axis in the regulation of NK cell responses in HCC and provide evidence in support of a potentially important role of anti-MICA/B mAb and IL-15 stimulation in HCC immunotherapy.

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Project description:Inflammatory responses initiate rapid production of IL-1 family cytokines, including IL-18. This cytokine is produced at high levels in inflammatory diseases, including allergy and autoimmunity, and is known to induce IgE production in mice. Here we provide evidence that IL-18 is directly coupled to induction of self-reactive IgM and IgG antibody responses and recruitment of innate B2 B cells residing in the marginal zone of the spleen. Moreover, the data suggest that the B-cell activation occurs predominantly in splenic extrafollicular plasma cell foci and is regulated by natural killer T (NKT) cells that prevent formation of mature germinal centers. We also find evidence that NKT cells control this type of B-cell activation via cytotoxicity mediated by both the perforin and CD95/CD178 pathways. Thus, NKT cells regulate innate antibody responses initiated by an inflammatory stimulus, suggesting a general mechanism that regulates B-cell behavior in inflammation and autoreactivity.

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Responses of IL-18- and IL-18 receptor-deficient pancreatic islets with convergence of positive and negative signals for the IL-18 receptor.

Project description:Pancreatic islets contain cells that produce IL-18 and cells that express IL-18 receptors. In experimentally induced diabetes, islet failure correlates with IL-18 levels and diabetes is delayed with blockade of endogenous IL-18. We studied islet-derived IL-18 and responses to IL-18 in a mouse model of islet allograft transplantation. In vitro, IL-18-stimulated islets produced nitric oxide, which closely matched islet apoptosis. By neutralizing IL-18 activity with IL-18 binding protein (IL-18BP), we observed that islets produce bioactive IL-18. In vivo, transgenic mice overproducing IL-18BP (IL-18BP-Tg) exhibited delayed hyperglycemia induced by beta cell toxic streptozotocin. Similarly, cultured IL-18BP-Tg islets were protected from streptozotocin-induced apoptosis. In the transplant model, islets grafted from WT to IL-18BP-Tg mice achieved prolonged normoglycemia (P = 0.031). Improved graft function was also observed by using IL-18-deficient islets transplanted into WT recipients, demonstrating that endogenous, islet-derived IL-18 mediates IL-18-driven graft damage. Unexpectedly, islets from mice deficient in IL-18 receptor alpha chain (IL-18R) exhibited rapid graft failure (P = 0.024; IL-18- versus IL-18R-deficient grafts in WT recipients). In related studies, IL-18R-deficient splenocytes and macrophages produced 2- to 3-fold greater amounts of IL-18, TNFalpha, macrophage inflammatory protein 1, macrophage inflammatory protein 2, and IFNgamma upon stimulation with Con A, Toll-like receptor 2 agonist, or anti-CD3 antibodies. These data reveal a role for islet-derived IL-18 activity during inflammation-mediated islet injury. Importantly, discrepancies between IL-18- and IL-18R-deficient cells suggest that IL-18Ralpha chain is used by an inflammation-suppressing signal.

| S-EPMC1636543 | biostudies-literature

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