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NK cell activation in visceral leishmaniasis requires TLR9, myeloid DCs, and IL-12, but is independent of plasmacytoid DCs.

ABSTRACT: Natural killer (NK) cells are sentinel components of the innate response to pathogens, but the cell types, pathogen recognition receptors, and cytokines required for their activation in vivo are poorly defined. Here, we investigated the role of plasmacytoid dendritic cells (pDCs), myeloid DCs (mDCs), Toll-like receptors (TLRs), and of NK cell stimulatory cytokines for the induction of an NK cell response to the protozoan parasite Leishmania infantum. In vitro, pDCs did not endocytose Leishmania promastigotes but nevertheless released interferon (IFN)-alpha/beta and interleukin (IL)-12 in a TLR9-dependent manner. mDCs rapidly internalized Leishmania and, in the presence of TLR9, produced IL-12, but not IFN-alpha/beta. Depletion of pDCs did not impair the activation of NK cells in L. infantum-infected mice. In contrast, L. infantum-induced NK cell cytotoxicity and IFN-gamma production were abolished in mDC-depleted mice. The same phenotype was observed in TLR9(-/-) mice, which lacked IL-12 expression by mDCs, and in IL-12(-/-) mice, whereas IFN-alpha/beta receptor(-/-) mice showed only a minor reduction of NK cell IFN-gamma expression. This study provides the first direct evidence that mDCs are essential for eliciting NK cell cytotoxicity and IFN-gamma release in vivo and demonstrates that TLR9, mDCs, and IL-12 are functionally linked to the activation of NK cells in visceral leishmaniasis.

SUBMITTER: Schleicher U

PROVIDER: S-EPMC2118560 | biostudies-literature |

REPOSITORIES: biostudies-literature

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NK cell survival mediated through the regulatory synapse with human DCs requires IL-15Ralpha.

Project description:DCs activate NK cells during innate immune responses to viral infections. However, the composition and kinetics of the immunological synapse mediating this interaction are largely unknown. Here, we report the rapid formation of an immunological synapse between human resting NK cells and mature DCs. Although inhibitory NK cell receptors were polarized to this synapse, where they are known to protect mature DCs from NK cell lysis, the NK cell also received activation signals that induced mobilization of intracellular calcium and CD69 upregulation. The high-affinity component of the receptor for IL-15, IL-15Ralpha, accumulated at the synapse center on NK cells, and blocking of IL-15Ralpha increased NK cell apoptosis and diminished NK cell survival during their interaction with DCs. Furthermore, IL-15Ralpha-deficient NK cells, obtained from donors with a history of infectious mononucleosis, showed diminished survival in culture with DCs. Synapse formation was required for IL-15Ralpha-mediated NK cell survival, because synapse disruption by adhesion molecule blocking decreased DC-induced NK cell survival. These results identify what we believe to be a novel regulatory NK cell synapse with hallmarks of spatially separated inhibitory and activating interactions at its center. We suggest that this synapse formation enables optimal NK cell activation by DCs during innate immune responses.

| S-EPMC2030458 | biostudies-literature

Combined in vitro IL-12 and IL-15 stimulation promotes cellular immune response in dogs with visceral leishmaniasis.

Project description:Domestic dogs are the main reservoir of Leishmania infantum, a causative agent of visceral leishmaniasis (VL). The number of human disease cases is associated with the rate of canine infection. Currently available drugs are not efficient at treating canine leishmaniasis (CanL) and months after the treatment most dogs show disease relapse, therefore the development of new drugs or new therapeutic strategies should be sought. In CanL, dogs lack the ability to mount a specific cellular immune response suitable for combating the parasite and manipulation of cytokine signaling pathway has the potential to form part of effective immunotherapeutic methods. In this study, recombinant canine cytokines (rcaIL-12, rcaIL-2, rcaIL-15 and rcaIL-7) and soluble receptor IL-10R1 (rcasIL-10R1), with antagonistic activity, were evaluated for the first time in combination (rcaIL-12/rcaIL-2, rcaIL-12/rcaIL-15, rcaIL-12/rcasIL-10R1, rcaIL-15/rcaIL-7) or alone (rcasIL-10R1) to evaluate their immunomodulatory capacity in peripheral blood mononuclear cells (PBMCs) from dogs with leishmaniasis. All the combinations of recombinant proteins tested were shown to improve lymphoproliferative response. Further, the combinations rcaIL-12/rcaIL-2 and rcaIL-12/rcaIL-15 promoted a decrease in programmed cell death protein 1 (PD-1) expression in lymphocytes. These same combinations of cytokines and rcaIL-12/rcasIL-10R1 induced IFN-γ and TNF-α production in PBMCs. Furthermore, the combination IL-12/IL-15 led to an increased in T-bet expression in lymphocytes. These findings are encouraging and indicate the use of rcaIL-12 and rcaIL-15 in future in vivo studies aimed at achieving polarization of cellular immune responses in dogs with leishmaniasis, which may contribute to the development of an effective treatment against CanL.

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Targeting IL-27 and/or IL-10 in Experimental Murine Visceral Leishmaniasis.

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| S-EPMC7646755 | biostudies-literature

Myeloid dendritic cells (DCs) of mice susceptible to paracoccidioidomycosis suppress T cell responses whereas myeloid and plasmacytoid DCs from resistant mice induce effector and regulatory T cells.

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| S-EPMC3639589 | biostudies-literature

Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis.

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Sarcoma IL-12 overexpression facilitates NK cell immunomodulation.

Project description:Interleukin-12 (IL-12) is an inflammatory cytokine that has demonstrated efficacy for cancer immunotherapy, but systemic administration has detrimental toxicities. Lentiviral transduction eliciting IL-12-producing human sarcoma for autologous reintroduction provides localized delivery for both innate and adaptive immune response augmentation. Sarcoma cell lines and primary human sarcoma samples were transduced with recombinant lentivirus engineering expression of human IL-12 (hu-IL-12). IL-12 expressing sarcomas were assessed in vitro and in vivo following implantation into humanized NSG and transgenic human IL-15 expressing (NSG.Tg(Hu-IL-15)) murine models. Lentiviral transduction (LV/hu-IL-12) of human osteosarcoma, Ewing sarcoma and rhabdomyosarcoma cell lines, as well as low-passage primary human sarcomas, engendered high-level expression of hu-IL-12. Hu-IL-12 demonstrated functional viability, eliciting specific NK cell-mediated interferon-γ (IFN-γ) release and cytotoxic growth restriction of spheroids in vitro. In orthotopic xenograft murine models, the LV/hu-IL-12 transduced human sarcoma produced detectable IL-12 and elicited an IFN-γ inflammatory immune response specific to mature human NK reconstitution in the NSG.Tg(Hu-IL-15) model while restricting tumor growth. We conclude that LV/hu-IL-12 transduction of sarcoma elicits a specific immune reaction and the humanized NSG.Tg(Hu-IL-15) xenograft, with mature human NK cells, can define in vivo anti-tumor effects and systemic toxicities. IL-12 immunomodulation through autologous tumor transduction and reintroduction merits exploration for sarcoma treatment.

| S-EPMC8050085 | biostudies-literature

NK Cell IL-10 Production Requires IL-15 and IL-10 Driven STAT3 Activation.

Project description:Natural killer (NK) cells can produce IFNγ or IL-10 to regulate inflammation and immune responses but the factors driving NK cell IL-10 secretion are poorly-defined. Here, we identified NK cell-intrinsic STAT3 activation as vital for IL-10 production during both systemic Listeria monocytogenes (Lm) infection and following IL-15 cytokine/receptor complex (IL15C) treatment for experimental cerebral malaria (ECM). In both contexts, conditional Stat3 deficiency in NK cells abrogated production of IL-10. Initial NK cell STAT3 phosphorylation was driven by IL-15. During Lm infection, this required capture or presentation of IL-15 by NK cell IL-15Rα. Persistent STAT3 activation was required to drive measurable IL-10 secretion and required NK cell expression of IL-10Rα. Survival-promoting effects of IL-15C treatment in ECM were dependent on NK cell Stat3 while NK cell-intrinsic deficiency for Stat3, Il15ra, or Il10ra abrogated NK cell IL-10 production and increased resistance against Lm. NK cell Stat3 deficiency did not impact production of IFNγ, indicating the STAT3 activation initiated by IL-15 and amplified by IL-10 selectively drives the production of anti-inflammatory IL-10 by responding NK cells.

| S-EPMC6736993 | biostudies-literature

Defective Induction of IL-27-Mediated Immunoregulation by Myeloid DCs in Multiple Sclerosis.

Project description:The purpose of this study was to examine whether myeloid dendritic cells (mDCs) from patients with multiple sclerosis (MS) and healthy controls (HCs) become similarly tolerogenic when exposed to IL-27 as this may represent a potential mechanism of autoimmune dysregulation. Our study focused on natural mDCs that were isolated from HCs and MS patient peripheral blood mononuclear cells (PBMCs). After a 24-h treatment with IL-27 ± lipopolysaccharide (LPS), the mDCs were either harvested to identify IL-27-regulated gene expression or co-cultured with naive T-cells to measure how the treated DC affected T-cell proliferation and cytokine secretion. mDCs isolated from HCs but not untreated MS patients became functionally tolerogenic after IL-27 treatment. Although IL-27 induced both HC and untreated MS mDCs to produce similar amounts of IL-10, the tolerogenic HC mDCs expressed PD-L2, IDO1, and SOCS1, while the non-tolerogenic untreated MS mDCs expressed IDO1 and IL-6R. Cytokine and RNA analyses identified two signature blocks: the first identified genes associated with mDC tolerizing responses to IL-27, while the second was associated with the presence of MS. In contrast to mDCs from untreated MS patients, mDCs from HCs and IFNb-treated MS patients became tolerogenic in response to IL-27. The genes differentially expressed in the different donor IL-27-treated mDCs may contain targets that regulate mDC tolerogenic responses.

| S-EPMC10179146 | biostudies-literature

Interleukin-27 (IL-27) Mediates Susceptibility to Visceral Leishmaniasis by Suppressing the IL-17-Neutrophil Response.

Project description:The relationship established between Leishmania infantum and the vertebrate host can lead to a self-healing infection or to the manifestation of visceral leishmaniasis, a chronic systemic infection associated with high rates of mortality. We hypothesized that regulatory cytokines, such as interleukin-27 (IL-27), play a role in susceptibility to L. infantum infection. IL-27 is a heterodimeric cytokine composed of IL-27p28 and EBi3 subunits which, when combined, bind to IL-27R, leading to STAT-1 and -3 activation, playing a role in the regulation of the immune response. We observed in this work that IL-27 regulates the Th1/Th17 profiles in a mouse model of visceral leishmaniasis (VL) caused by L. infantum We showed here that the pathogen recognition by endosomal Toll-like receptors triggers a type I interferon (IFN) response, which acts through the type I IFN receptor and interferon regulatory factor 1 to induce IL-27 production by macrophages. Furthermore, IL-27 plays a major regulatory role in vivo, because Ebi3(-/-) mice can efficiently control parasite replication despite reduced levels of IFN-γ compared to wild-type mice. On the other hand, the absence of Ebi3 leads to exacerbated IL-17A production in the infected organs as well as in a coculture system, suggesting a direct regulatory action of IL-27 during L. infantum infection. As a consequence of exacerbated IL-17A in Ebi3(-/-) mice, a greater neutrophil influx was observed in the target organs, playing a role in parasite control. Thus, this work unveiled the molecular steps of IL-27 production after L. infantum infection and demonstrated its regulatory role in the IL-17A-neutrophil axis.

| S-EPMC4962641 | biostudies-literature

Is the polymorphism at position -1082 of IL-10 gene associated with visceral leishmaniasis?

Project description:BACKGROUND: Immune responses play critical roles in the leishmaniasis eradication. IL-10 is a key regulator of immune responses, and the polymorphisms within its promoter region are associated with alteration in its expression. Therefore, this study was designed to examine the correlation between polymorphism at the -1082 position of the IL-10 gene and visceral leishmaniasis (VL). METHODS: The IL-10 -1082 polymorphism and anti-Leishmania antibody titration were examined in 110 patients with clinical presentation of VL and seropositive for the Leishmania (group 1), 74 seropositive patients but without clinical presentation (group 2) and 113 healthy controls (group 3) using the PCR-RFLP and immunofluorescence techniques, respectively. RESULTS: The polymorphism at IL-10 -1082 (A/G) position was significantly associated with VL and A/G genotype was significantly higher in VL patients when compared to the groups 2 and 3 (P< 0.001). However, the results demonstrated that the A and G alleles were not associated with VL (P= 0.263). CONCLUSIONS: Previous investigations have shown that the polymorphism at the -1082 position of the IL-10 gene can influence its expression and also it has been proved that IL-10 level was increased during VL. Our results suggest that the A/G genotype may be considered as a risk factor for VL.

| S-EPMC4411907 | biostudies-other

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