IFN type I and type II independent enhancement of B cell TLR7 expression by natural killer cells.
Ontology highlight
ABSTRACT:
SUBMITTER: Sinha S
PROVIDER: S-EPMC3441313 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Systemic lupus erythematosus is an autoimmune disease characterized by increased type I IFNs, autoantibodies, and inflammatory-mediated multiorgan damage. TLR7 activation is an important contributor to systemic lupus erythematosus pathogenesis, but the mechanisms by which type I IFNs participate in TLR7-driven pathologic conditions remain uncertain. In this study, we examined the requirement for type I IFNs in TLR7-stimulated lupus nephritis. Lupus-prone NZM2328, INZM (which lack a functional type I IFN receptor), and NZM2328 IL-1?-/- mice were treated at 10 wk of age on the right ear with R848 (TLR7 agonist) or control (DMSO). Autoantibody production and proteinuria were assessed throughout treatment. Multiorgan inflammation was assessed at the time of decline in health. Renal infiltrates and mRNA expression were also examined after 14 d of treatment. Both NZM2328 and INZM mice exhibited a decline in survival after 3-4 wk of R848 but not vehicle treatment. Development of splenomegaly and liver inflammation were dependent on type I IFN. Interestingly, autoantibody production, early renal infiltration of dendritic cells, upregulation of IL-1?, and lupus nephritis occurred independent of type I IFN signaling. Development of TLR7-driven lupus nephritis was not abolished by the deletion of IL-1?. Thus, although IFN-? is sufficient to induce nephritis acceleration, our data emphasize a critical role for IFN-independent signaling in TLR7-mediated lupus nephritis. Further, despite upregulation of IL-1? after TLR7 stimulation, deletion of IL-1? is not sufficient to reduce lupus nephritis development in this model.
| S-EPMC6039244 | biostudies-literature
Project description:The TLR7 agonist imiquimod has been used successfully as adjuvant for skin treatment of virus-associated warts and basal cell carcinoma. The effects of skin TLR7 triggering on respiratory leukocyte populations are unknown. In a placebo-controlled experimental animal study we have used multicolour flow cytometry to systematically analyze the modulation of respiratory leukocyte subsets after skin administration of imiquimod. Compared to placebo, skin administration of imiquimod significantly increased respiratory dendritic cells (DC) and natural killer cells, whereas total respiratory leukocyte, alveolar macrophages, classical CD4+ T helper and CD8+ T killer cell numbers were not or only moderately affected. DC subpopulation analyses revealed that elevation of respiratory DC was caused by an increase of respiratory monocytic DC and CD11b(hi) DC subsets. Lymphocyte subpopulation analyses indicated a marked elevation of respiratory natural killer cells and a significant reduction of B lymphocytes. Analysis of cytokine responses of respiratory leukocytes after stimulation with Klebsiella pneumonia indicated reduced IFN-γ and TNF-α expression and increased IL-10 and IL-12p70 production after 7 day low dose skin TLR7 triggering. Additionally, respiratory NK cytotoxic activity was increased after 7d skin TLR7 triggering. In contrast, lung histology and bronchoalveolar cell counts were not affected suggesting that skin TLR7 stimulation modulated respiratory leukocyte composition without inducing overt pulmonary inflammation. These data suggest the possibility to modulate respiratory leukocyte composition and respiratory cytokine responses against pathogens like Klebsiella pneumonia through skin administration of a clinically approved TLR7 ligand. Skin administration of synthetic TLR7 ligands may represent a novel, noninvasive means to modulate respiratory immunity.
| S-EPMC3425551 | biostudies-literature
Project description:Natural killer T (NKT) cells are αβ T cell receptor (TCR) expressing innate-like T cells that display natural killer (NK) cell markers. Based on TCR characteristics, they are divided into two groups restricted to the MHC class I-like molecule CD1d. Type I NKT cells, most extensively studied, are identified by a semi-invariant Vα14-Jα18 (mouse, Vα24-Jα18 in humans) TCR reactive to the prototypic ligand α-galactosylceramide presented on CD1d. In contrast, type II NKT cells display diverse TCR reacting to different CD1d-presented ligands. There are no reagents that identify all type II NKT cells, limiting their exploration. Here, we searched for novel type II NKT cells by comparing Jα18-/- MHCII-/- mice that harbour type II but not type I NKT cells, and CD1d-/- MHCII-/- mice, lacking all NKT cells. We identified significantly larger populations of CD4+ and CD4- CD8- (double negative, DN) TCRβ+ cells expressing NKG2D or NKG2A/C/E in Jα18-/- MHCII-/- mice compared with CD1d-/- MHCII-/- mice, suggesting that 30%-50% of these cells were type II NKT cells. They expressed CD122, NK1.1, CXCR3 and intermediate/low levels of CD45RB. Further, the CD4+ subset was CD69+ , while the DN cells were CD49b+ and CD62L+ . Both subsets expressed the NKT cell-associated promyelocytic leukaemia zinc finger (PLZF) transcription factor and Tbet, while fewer cells expressed RORγt. NKG2D+ CD4+ and DN populations were producers of IFN-γ, but rarely IL-4 and IL-17. Taken together, we identify a novel subset of primary CD4+ and DN type II NKT cells that expresses NKG2 receptors have typical NKT cell phenotypes and a TH1-like cytokine production.
| S-EPMC6851763 | biostudies-literature
Project description:TLR7 is associated with development of systemic lupus erythematosus (SLE), but the underlying mechanisms are incompletely understood. Although TLRs are known to activate type I IFN (T1IFN) signaling, the role of T1IFN and IFN-? signaling in differential regulation of TLR7-mediated Ab-forming cell (AFC) and germinal center (GC) responses, and SLE development has never been directly investigated. Using TLR7-induced and TLR7 overexpression models of SLE, we report in this study a previously unrecognized indispensable role of TLR7-induced IFN-? signaling in promoting AFC and GC responses, leading to autoreactive B cell and SLE development. T1IFN signaling in contrast, only modestly contributed to autoimmune responses and the disease process in these mice. TLR7 ligand imiquimod treated IFN-? reporter mice show that CD4+ effector T cells including follicular helper T (Tfh) cells are the major producers of TLR7-induced IFN-?. Transcriptomic analysis of splenic tissues from imiquimod-treated autoimmune-prone B6.Sle1b mice sufficient and deficient for IFN-?R indicates that TLR7-induced IFN-? activates multiple signaling pathways to regulate TLR7-promoted SLE. Conditional deletion of Ifngr1 gene in peripheral B cells further demonstrates that TLR7-driven autoimmune AFC, GC and Tfh responses and SLE development are dependent on IFN-? signaling in B cells. Finally, we show crucial B cell-intrinsic roles of STAT1 and T-bet in TLR7-driven GC, Tfh and plasma cell differentiation. Altogether, we uncover a nonredundant role for IFN-? and its downstream signaling molecules STAT1 and T-bet in B cells in promoting TLR7-driven AFC, GC, and SLE development whereas T1IFN signaling moderately contributes to these processes.
| S-EPMC7002260 | biostudies-literature
Project description:Natural killer (NK) cells are important antiviral effector cells and also involved in tumor clearance. NK cells express IFNAR, rendering them responsive to Type I IFNs. To evaluate Type I IFN-mediated modulation of NK cell functions, individual Type I IFNs subtypes were assessed for their ability to activate NK cells. Different Type I IFN subtypes displayed a broad range in the capacity to induce and modulate NK cell activation and degranulation, measured by CD69 and CD107a expression in response to leukemia cell line K562. When including biological sex as a variable in the analysis, transwell co-cultures of NK cells with either male- or female-derived PBMCs or pDCs stimulated with the TLR7/8 agonist CL097 showed that NK cells were more activated by CL097-stimulated cells derived from females. These sex-specific differences were linked to higher CL097-induced IFNα production by pDCs derived from females, indicating an extrinsic sex-specific effect of Type I IFNs on NK cell function. Interestingly, in addition to the extrinsic effect, we also observed NK cell-intrinsic sex differences, as female NK cells displayed higher activation levels after IFNα-stimulation and after co-culture with CL097-stimulated pDCs, suggesting higher activation of IFNα-signaling transduction in female NK cells. Taken together, the results from these studies identify both extrinsic and intrinsic sex-specific differences in Type I IFN-dependent NK cell functions, contributing to a better understanding of sex-specific differences in innate immunity.
| S-EPMC10757368 | biostudies-literature
Project description:Natural killer T (NKT) cells recognize glycolipids presented by CD1d. The first antigen described, ?-galactosyl ceramide (?GalCer), is a potential anticancer agent whose activity depends upon IFN-? secretion. We report two analogs of ?GalCer based on a naturally occurring glycosphingolipid, plakoside A. These compounds induce enhanced IFN-? that correlates with detergent-resistant binding to CD1d and an increased stability of the lipid-CD1d complexes on antigen-presenting cells. Structural analysis on one of the analogs indicates that it is more deeply bound inside the CD1d groove, suggesting tighter lipid-CD1d interactions. To our knowledge, this is the first example in which structural information provides an explanation for the increased lipid-CD1d stability, likely responsible for the Th1 bias. We provide insights into the mechanism of IFN-?-inducing compounds, and because our compounds activate human NKT cells, they could have therapeutic utility.
| S-EPMC3246403 | biostudies-literature
Project description:Rhinovirus (RV), the causative agent of the common cold, causes only mild upper respiratory tract infections in healthy individuals, but can cause longer lasting and more severe pulmonary infections in people with chronic lung diseases and in the setting of immune suppression or immune deficiency. RV-infected lung structural cells release type I interferon (IFN-I), initiating the immune response, leading to protection against viruses in conjunction with migratory immune cells. However, IFN-I release is deficient in some people with asthma. Innate immune cells, such as natural killer (NK) cells, are proposed to play major roles in the control of viral infections, and may contribute to exacerbations of chronic lung diseases, such as asthma. In this study, we characterized the NK cell response to RV infection using an in vitro model of infection in healthy individuals, and determined the extent to which IFN-I signaling mediates this response. The results indicate that RV stimulation in vitro induces NK cell activation in healthy donors, leading to degranulation and the release of cytotoxic mediators and cytokines. IFN-I signaling was partly responsible for NK cell activation and functional responses to RV. Overall, our findings suggest the involvement of NK cells in the control of RV infection in healthy individuals. Further understanding of NK cell regulation may deepen our understanding of the mechanisms that contribute to susceptibility to RV infections in asthma and other chronic lung diseases.
| S-EPMC7609819 | biostudies-literature
Project description:UnlabelledInnate immune mechanisms leading to liver injury subsequent to chronic alcohol ingestion are poorly understood. Natural killer T (NKT) cells, enriched in the liver and comprised of at least two distinct subsets, type I and II, recognize different lipid antigens presented by CD1d molecules. We have investigated whether differential activation of NKT cell subsets orchestrates inflammatory events leading to alcoholic liver disease (ALD). We found that after chronic plus binge feeding of Lieber-DeCarli liquid diet in male C57BL/6 mice, type I, but not type II, NKT cells are activated, leading to recruitment of inflammatory Gr-1(high) CD11b(+) cells into the liver. A central finding is that liver injury after alcohol feeding is dependent upon type I NKT cells. Thus, liver injury is significantly inhibited in Jα18(-/-) mice deficient in type I NKT cells as well as after their inactivation by sulfatide-mediated activation of type II NKT cells. Furthermore, we have identified a novel pathway involving all-trans retinoic acid (ATRA) and its receptor (RARγ) signaling that inhibits type I NKT cells and, consequently, ALD. A semiquantitative polymerase chain reaction analysis of hepatic gene expression of some of the key proinflammatory molecules shared in human disease indicated that their up-regulation in ALD is dependent upon type I NKT cells.ConclusionsType I, but not type II, NKT cells become activated after alcohol feeding. Type I NKT cell-induced inflammation and neutrophil recruitment results in liver tissue damage whereas type II NKT cells protect from injury in ALD. Inhibition of type I NKT cells by retinoids or by sulfatide prevents ALD. Given that the CD1d pathway is highly conserved between mice and humans, NKT cell subsets might be targeted for potential therapeutic intervention in ALD.
| S-EPMC4376634 | biostudies-literature
Project description:Lung macrophage (LM) is vital in host defence against bacterial infections. However, the influence of other innate immune cells on its function, including the polarisation of different subpopulations, remains poorly understood. This study examined the polarisation of LM subpopulations (monocytes/undifferentiated macrophages (Mo/Mφ), interstitial macrophages (IM), and alveolar macrophages (AM)). We further assessed the effect of invariant natural killer T cells (iNKT) on LM polarisation in a protective function against Chlamydia muridarum, an obligate intracellular bacterium, and respiratory tract infection. We found a preferentially increased local Mo/Mφ and IMs with a significant shift to a type-1 macrophage (M1) phenotype and higher expression of iNOS and TNF-α. Interestingly, during the same infection, the alteration of macrophage subpopulations and the shift towards M1 was much less in iNKT KO mice. More importantly, functional testing by adoptively transferring LMs isolated from iNKT KO mice (iNKT KO-Mφ) conferred less protection than those isolated from wild-type mice (WT-Mφ). Further analyses showed significantly reduced gene expression of the JAK/STAT signalling pathway molecules in iNKT KO-Mφ. The data show an important role of iNKT in promoting LM polarisation to the M1 direction, which is functionally relevant to host defence against a human intracellular bacterial infection. The alteration of JAK/STAT signalling molecule gene expression in iNKT KO-Mφ suggests the modulating effect of iNKT is likely through the JAK/STAT pathway.
| S-EPMC10813948 | biostudies-literature
Project description:UNLABELLED:Ribavirin (RBV) is an important component of interferon (IFN)-based and direct antiviral treatment regimens for hepatitis C virus (HCV) infection. Immunomodulation, in particular improvement of the host IFN response, has been proposed as RBV's mechanism of action. Natural killer (NK) cells are sensitive biomarkers for IFN-?/? receptor signaling, as NK cell cytotoxicity and IFN-? production are regulated by signal transducer and activator of transcription (STAT)1- and STAT4-phosphorylation, respectively. Specifically, pSTAT1-dependent NK cell cytotoxicity increases and pSTAT4-dependent IFN-? production decreases in response to endogenous, virus-induced IFN-? and during IFN-?-based therapy. To assess whether RBV has a direct effect on NK cells and/or improves the IFN-? response of NK cells in the presence of IFN-?, we prospectively studied 22 HCV patients with and 32 patients without 4 weeks of RBV pretreatment, who all received subsequent pegylated (Peg)IFN/ribavirin combination therapy. During RBV pretreatment, both the frequency of CD56(dim) NK cells with cytotoxic effector functions and the frequency of CD56(bright) NK cells with the capacity to produce IFN-? decreased (P?=?0.049 and P?=?0.001, respectively). In vitro or in vivo exposure of NK cells to RBV improved the pSTAT4 (P?<?0.01) but not pSTAT1 response of NK cells to subsequent stimulation with IFN-?. This was associated with an increase in IFN-? production but not cytotoxicity of NK cells during subsequent IFN-?-based therapy. The frequency of IFN-?-producing NK cells was greater in fast second-phase virological responders than in slow responders. CONCLUSION:RBV enhances the pSTAT4 and IFN-? response of NK cells to IFN-?-stimulation.
| S-EPMC4469648 | biostudies-literature