Mechanistic target of rapamycin complex 1 is critical for invariant natural killer T-cell development and effector function.
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ABSTRACT:
SUBMITTER: Shin J
PROVIDER: S-EPMC3939904 | biostudies-other | 2014 Feb
REPOSITORIES: biostudies-other
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Project description:We report that Histone Deacetylase 7 (HDAC7) controls the thymic effector programming of Natural Killer T (NKT) cells, and that interference with this function contributes to tissue-specific autoimmunity. Gain of HDAC7 function in thymocytes blocks both negative selection and NKT development, and diverts Vα14/Jα18 TCR transgenic thymocytes into a Tconv-like lineage. Conversely, HDAC7 deletion promotes thymocyte apoptosis and causes expansion of innate-effector cells. Investigating the mechanisms involved, we found that HDAC7 binds PLZF and modulates PLZF-dependent transcription. Moreover, HDAC7 and many of its transcriptional targets are human risk loci for IBD and PSC, autoimmune diseases that strikingly resemble the disease we observe in HDAC7 gain-of-function in mice. Importantly, reconstitution of iNKT cells in these mice mitigated their disease, suggesting that the combined defects in negative selection and iNKT cells due to altered HDAC7 function can cause tissue-restricted autoimmunity, a finding that may explain the association between HDAC7 and hepatobiliary autoimmunity.
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Project description:Natural killer (NK) cells are cytotoxic innate lymphoid cells that participate in anti-tumour and anti-viral immune responses. Their ability to rapidly destroy abnormal cells and to enhance the anti-cancer function of dendritic cells, CD8+ T cells, and macrophages makes them an attractive target for immunotherapeutic strategies. The development of approaches that augment NK-cell activation against cancer is currently under intense preclinical and clinical research and strategies include chimeric antigen receptor NK cells, NK-cell engagers, cytokines, and immune checkpoint inhibitors. In this review, we highlight recent advances in NK-cell therapeutic development and discuss their potential to add to our armamentarium against cancer.
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Project description:The gut microbiota regulates chronic inflammation and has been implicated in the pathogenesis of a broad spectrum of disease including autoimmunity and cancer. Microbial short-chain fatty acids (SCFAs) e.g., butyrate have demonstrated immunomodulatory effects and are thought to be key mediators of the host-microbiome interaction. Here, we investigated the effect of butyrate on effector functions of blood derived human NK cells stimulated for 18 h with a combination of IL-12/IL-15, a potent mix of cytokines that drive NK cell activation. We show that butyrate has a strong anti-inflammatory effect on NK cells. NK cells cultured in the presence of butyrate expressed lower levels of activating receptors (TRAIL, NKp30, NKp44) and produced lower levels of cytokines (IFNγ, TNF-α, IL-22, granzyme B, granzyme A, perforin) in response to IL-12/IL-15. Butyrate restricted NK cell function by downregulation of mTORC1 activity, c-Myc mRNA expression and metabolism. Using a shotgun proteomic approach, we confirmed the effect of butyrate on NK cell cytokine signaling and metabolism and identified BRD2, MAT2A and EHD1 as downstream mediators of these effects. This insight into the immunomodulatory activity of butyrate on human NK cell function might help to develop new ways to limit NK cell function during chronic inflammation.
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Project description:Background The mechanistic target of rapamycin complex 1 ( mTORC 1) is an important intracellular energy sensor that regulates gene expression and protein synthesis through its downstream signaling components, the S6-kinase and the ribosomal S6 protein. Recently, signaling arising from mTORC 1 has been implicated in regulation of the cardiovascular system with implications for disease. Here, we examined the contribution of mTORC 1 signaling to the regulation of vascular function. Methods and Results Activation of mTORC 1 pathway in aortic rings with leucine or an adenoviral vector expressing a constitutively active S6-kinase reduces endothelial-dependent vasorelaxation in an mTORC 1-dependent manner without affecting smooth muscle relaxation responses. Moreover, activation of mTORC 1 signaling in endothelial cells increases reactive oxygen species ( ROS ) generation and ROS gene expression resulting in a pro-oxidant gene environment. Blockade of ROS signaling with Tempol restores endothelial function in vascular rings with increased mTORC 1 activity indicating a crucial interaction between mTORC 1 and ROS signaling. We then tested the role of nuclear factor-κB transcriptional complex in connecting mTORC 1 and ROS signaling in endothelial cells. Blockade of inhibitor of nuclear factor κ-B kinase subunit β activity with BMS -345541 prevented the increased ROS generation associated with increased mTORC 1 activity in endothelial cells but did not improve vascular endothelial function in aortic rings with increased mTORC 1 and ROS signaling. Conclusions These results implicate mTORC 1 as a critical molecular signaling hub in the vascular endothelium in mediating vascular endothelial function through modulation of ROS signaling.
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Project description:Invariant natural killer T (iNKT) cells belong to a subset of lymphocytes bridging innate and acquired immunity. We demonstrated that osteopontin (OPN) is involved in the activation of iNKT cells. In the present work, we examined whether OPN affects development and function of iNKT cells. We found that the number of peripheral iNKT cells was significantly reduced in OPN-deficient mice compared with wild-type mice. Although the number of thymic iNKT cells was not different between WT and OPN-deficient mice, intrathymic iNKT cell maturation was impaired in OPN-deficient mice. iNKT cell function was also significantly altered in OPN-deficient mice, as evidenced by (i) deficient down-regulation of iNKT cell receptor, (ii) reduction of IL-4 production while preserving production of IFN-gamma, and (iii) reduction of Fas ligand (FasL) expression, leading to reduced Fas/FasL-dependent cytotoxicity against hepatocytes. Importantly, activation of the transcription factors NFAT2 (nuclear factor of activated T cells 2) and GATA-3 was impaired, whereas activation of T-bet was preserved in iNKT cells of OPN-deficient mice. These data collectively indicate that OPN plays a pivotal role not only in the development, but also in the function of iNKT cells.
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Project description:IntroductionLabor induces a myriad of changes in placental gene expression. These changes may represent a physiological adaptation inhibiting placental cellular processes associated with a high demand for oxygen and energy (e.g., protein synthesis and active transport) thereby promoting oxygen and glucose transfer to the fetus. We hypothesized that mechanistic target of rapamycin complex 1 (mTORC1) signaling, a positive regulator of trophoblast protein synthesis and amino acid transport, is inhibited by labor.MethodsPlacental tissue was collected from healthy, term pregnancies (n = 15 no-labor; n = 12 labor). Activation of Caspase-1, IRS1/Akt, STAT, mTOR, and inflammatory signaling pathways was determined by Western blot. NFĸB p65 and PPARγ DNA binding activity was measured in isolated nuclei.ResultsLabor increased Caspase-1 activation and mTOR complex 2 signaling, as measured by phosphorylation of Akt (S473). However, mTORC1 signaling was inhibited in response to labor as evidenced by decreased phosphorylation of mTOR (S2448) and 4EBP1 (T37/46 and T70). Labor also decreased NFĸB and PPARγ DNA binding activity, while having no effect on IRS1 or STAT signaling pathway.Discussion and conclusionSeveral placental signaling pathways are affected by labor, which has implications for experimental design in studies of placental signaling. Inhibition of placental mTORC1 signaling in response to labor may serve to down-regulate protein synthesis and amino acid transport, processes that account for a large share of placental oxygen and glucose consumption. We speculate that this response preserves glucose and oxygen for transfer to the fetus during the stressful events of labor.
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Project description:The mammalian target of rapamycin (mTOR) senses and incorporates different environmental cues via the two signaling complexes mTOR complex 1 (mTORC1) and mTORC2. As a result, mTOR controls cell growth and survival, and also shapes different effector functions of the cells including immune cells such as T cells. We demonstrate in this article that invariant NKT (iNKT) cell development is controlled by mTORC2 in a cell-intrinsic manner. In mice deficient in mTORC2 signaling because of the conditional deletion of the Rictor gene, iNKT cell numbers were reduced in the thymus and periphery. This is caused by decreased proliferation of stage 1 iNKT cells and poor development through subsequent stages. Functionally, iNKT cells devoid of mTORC2 signaling showed reduced number of IL-4-expressing cells, which correlated with a decrease in the transcription factor GATA-3-expressing cells. However, promyelocytic leukemia zinc-finger (PLZF), a critical transcription factor for iNKT cell development, is expressed at a similar level in mTORC2-deficient iNKT cells compared with that in the wild type iNKT cells. Furthermore, cellular localization of PLZF was not altered in the absence of mTOR2 signaling. Thus, our study reveals the PLZF-independent mechanisms of the development and function of iNKT cells regulated by mTORC2.
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Project description:The mechanistic target of rapamycin (mTOR) exists in two complexes that regulate diverse cellular processes. mTOR complex 1 (mTORC1), the canonical target of rapamycin, has been well studied, whereas the physiological role of mTORC2 remains relatively uncharacterized. In mice in which the mTORC2 component Rictor is deleted in liver [Rictor-knockout (RKO) mice], we used genomic and phosphoproteomic analyses to characterize the role of hepatic mTORC2 in vivo. Overnight food withdrawal followed by refeeding was used to activate mTOR signaling. Rapamycin was administered before refeeding to specify mTORC2-mediated events. Hepatic mTORC2 regulated a complex gene expression and post-translational network that affects intermediary metabolism, ribosomal biogenesis, and proteasomal biogenesis. Nearly all changes in genes related to intermediary metabolic regulation were replicated in cultured fetal hepatocytes, indicating a cell-autonomous effect of mTORC2 signaling. Phosphoproteomic profiling identified mTORC2-related signaling to 144 proteins, among which were metabolic enzymes and regulators. A reduction of p38 MAPK signaling in the RKO mice represents a link between our phosphoproteomic and gene expression results. We conclude that hepatic mTORC2 exerts a broad spectrum of biological effects under physiological conditions. Our findings provide a context for the development of targeted therapies to modulate mTORC2 signaling.
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Project description:We previously showed that potassium channel tetramerization domain containing 9 (KCTD9) is aberrantly expressed in natural killer (NK) cells in patients with hepatitis B virus-associated acute-on-chronic liver failure and mice with experimental fulminant hepatitis. However, the mechanism underlying the regulation of NK cell function and fulminant hepatitis progression by KCTD9 is unknown. Here, we investigated the role of Kctd9 in regulation of early development, maturation, and function of NK cells using Kctd9-knockout mice. Compared to wild-type mice, Kctd9-deficient mice exhibited impaired NK cell lineage commitment, as evidenced by selective reduction in the refined NK progenitors, and incomplete NK cell maturation, as manifested by a higher proportion of CD11b- NK cells and a lower percentage of CD11b+ NK cells with high proliferative potential. Moreover, Kctd9-depleted NK cells displayed insufficient IFN-γ production, degranulation, and granzyme B production in response to cytokine stimulation, and attenuated cytotoxicity to tumor cells in vitro. The defect in NK cells was further supported by ameliorated liver damage and improved survival in Kctd9-deficient mice following murine hepatitis virus strain-3 (MHV-3) infection, which otherwise leads to immune-mediated fulminant hepatitis, a phenotype homologous to that caused by NK cell depletion in wild-type mice. Further investigation to identify the underlying mechanism revealed that Kctd9 deficiency hindered the expression of transcription factors, including Ets1, Nfil3, Eomes, and Id2 in NK cells. Collectively, our data reveal that Kctd9 acts as a novel regulator for NK cell commitment, maturation, and effector function.
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Project description:Semi-invariant natural killer T (iNKT) cells are self-reactive lymphocytes, yet how this lineage attains self-tolerance remains unknown. iNKT cells constitutively express high levels of Nr4a1-encoded Nur77, a transcription factor that integrates signal strength downstream of the T cell receptor (TCR) within activated thymocytes and peripheral T cells. The function of Nur77 in iNKT cells is unknown. Here we report that sustained Nur77 overexpression (Nur77tg) in mouse thymocytes abrogates iNKT cell development. Introgression of a rearranged V?14-J?18 TCR-? chain gene into the Nur77tg (Nur77tg;V?14tg) mouse rescued iNKT cell development up to the early precursor stage, stage 0. iNKT cells in bone marrow chimeras that reconstituted thymic cellularity developed beyond stage 0 precursors and yielded IL-4-producing NKT2 cell subset but not IFN-?-producing NKT1 cell subset. Nonetheless, the developing thymic iNKT cells that emerged in these chimeras expressed the exhaustion marker PD1 and responded poorly to a strong glycolipid agonist. Thus, Nur77 integrates signals emanating from the TCR to control thymic iNKT cell tolerance induction, terminal differentiation, and effector functions.
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