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Selenoproteins mediate T cell immunity through an antioxidant mechanism.

ABSTRACT: Selenium is an essential dietary element with antioxidant roles in immune regulation, but there is little understanding of how this element acts at the molecular level in host defense and inflammatory disease. Selenium is incorporated into the amino acid selenocysteine (Sec), which in turn is inserted into selenoproteins in a manner dependent on Sec tRNA([Ser]Sec). To investigate the molecular mechanism that links selenium to T cell immunity, we generated mice with selenoprotein-less T cells by cell type-specific ablation of the Sec tRNA([Ser]Sec) gene (trsp). Herein, we show that these mutant mice exhibit decreased pools of mature T cells and a defect in T cell-dependent antibody responses. We also demonstrate that selenoprotein deficiency leads to oxidant hyperproduction in T cells and thereby suppresses T cell proliferation in response to T cell receptor stimulation. These findings offer novel insights into immune function of selenium and physiological antioxidants.

SUBMITTER: Shrimali RK

PROVIDER: S-EPMC2459287 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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Selenoproteins mediate T cell immunity through an antioxidant mechanism.

Shrimali Rajeev K RK Irons Robert D RD Carlson Bradley A BA Sano Yasuyo Y Gladyshev Vadim N VN Park Jin Mo JM Hatfield Dolph L DL

The Journal of biological chemistry 20080516 29

Selenium is an essential dietary element with antioxidant roles in immune regulation, but there is little understanding of how this element acts at the molecular level in host defense and inflammatory disease. Selenium is incorporated into the amino acid selenocysteine (Sec), which in turn is inserted into selenoproteins in a manner dependent on Sec tRNA([Ser]Sec). To investigate the molecular mechanism that links selenium to T cell immunity, we generated mice with selenoprotein-less T cells by ...[more]

PMID: 18487203

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Project description:BackgroundAs Traditional Chinese Medicine (TCM) drugs, Huangqi and Danshen are always applied in combination for spinal cord injury (SCI) treatment based on the compatibility theory of TCM. Astragalus Polysaccharidesis (APS) and Tanshinone IIA (TSIIA) are the main active ingredients of Huangqi and Danshen, and they both possess neuroprotective effects through antioxidant activities. However, low solubility and poor bioavailability have greatly limited their application. In recent years, selenium nanoparticles (SeNPs) have drawn enormous attention as potential delivery carrier for antioxidant drugs.ResultsIn this study, TCM active ingredients-based SeNPs surface decorated with APS and loaded with TSIIA (TSIIA@SeNPs-APS) were successfully synthesized under the guidance of the compatibility theory of TCM. Such design improved the bioavailability of APS and TSIIA with the benefits of high stability, efficient delivery and highly therapeutic efficacy for SCI treatment illustrated by an improvement of the antioxidant protective effects of APS and TSIIA. The in vivo experiments indicated that TSIIA@SeNPs-APS displayed high efficiency of cellular uptake and long retention time in PC12 cells. Furthermore, TSIIA@SeNPs-APS had a satisfactory protective effect against oxidative stress-induced cytotoxicity in PC12 cells by inhibiting excessive reactive oxygen species (ROS) production, so as to alleviate mitochondrial dysfunction to reduce cell apoptosis and S phase cell cycle arrest, and finally promote cell survival. The in vivo experiments indicated that TSIIA@SeNPs-APS can protect spinal cord neurons of SCI rats by enhancing GSH-Px activity and decreasing MDA content, which was possibly via the metabolism of TSIIA@SeNPs-APS to SeCys2 and regulating antioxidant selenoproteins to resist oxidative stress-induced damage.ConclusionsTSIIA@SeNPs-APS exhibited promising therapeutic effects in the anti-oxidation therapy of SCI, which paved the way for developing the synergistic effect of TCM active ingredients by nanotechnology to improve the efficacy as well as establishing novel treatments for oxidative stress-related diseases associated with Se metabolism and selenoproteins regulation.

Project description:BackgroundIn situ vaccination-induced local inflammatory response resulted in the establishment of a pool of tissue-resident memory T (TRM) cells and new vessels after the resolution of inflammation. TRM cells have received increasing attention; however, the role of new vessels in protective response is still unknown.Materials and methodsWe performed the laparotomy to access the stomach and injected alum-based vaccine into the gastric subserous layer (GSL). At 28 days post vaccination, a parabiosis mouse model along with depletion of anti-CD90.2 antibody was employed to explore the function of perivascular lymphocyte clusters in recall responses. The composition of the gastric lymphocyte clusters was analyzed by immunofluorescence staining. Antibody responses were detected using ELISA. Gastric lymphocytes were analyzed using flow cytometry.ResultsGSL vaccination induced the formation of new vessels in the inflamed region. These new vessels were different from native vessels in that they were generally accompanied by perivascular lymphocyte clusters that mainly consisted of CD90-expressing cells. Additionally, histological analysis revealed the presence of CD4+ and CD8+ T cells in the perivascular lymphocyte clusters. Administration of a dose of an anti-CD90.2 antibody to GSL-vaccinated mice resolved these clusters. The efficacy of protection was compared in the parabiosis mice. Upon challenge, the presence of perivascular lymphocyte clusters was responsible for the fast recall response, as depletion of these clusters by CD90.2 antibody administration resulted in decreased expressions of VCAM-1, Madcam-1, and TNF-α, as well as lower recruitment of proinflammatory immune cells, decreased antibody levels, and poor protection.ConclusionsOur research demonstrates that in situ vaccination-induced regional inflammatory response contributes to optimal recall response not only by establishing a CD4+ TRM pool but also by creating an "expressway," i.e., perivascular lymphocyte cluster.

Project description:The essential micronutrient Selenium (Se) is co-translationally incorporated as selenocysteine into proteins. Selenoproteins contain one or more selenocysteines and are vital for optimum immunity. Interestingly, many pathogenic bacteria utilize Se for various biological processes suggesting that Se may play a role in bacterial pathogenesis. A previous study had speculated that Francisella tularensis, a facultative intracellular bacterium and the causative agent of tularemia, sequesters Se by upregulating Se-metabolism genes in type II alveolar epithelial cells. Therefore, we investigated the contribution of host vs. pathogen-associated selenoproteins in bacterial disease using F. tularensis as a model organism. We found that F. tularensis was devoid of any Se utilization traits, neither incorporated elemental Se, nor exhibited Se-dependent growth. However, 100% of Se-deficient mice (0.01 ppm Se), which express low levels of selenoproteins, succumbed to F. tularensis-live vaccine strain pulmonary challenge, whereas 50% of mice on Se-supplemented (0.4 ppm Se) and 25% of mice on Se-adequate (0.1 ppm Se) diet succumbed to infection. Median survival time for Se-deficient mice was 8 days post-infection while Se-supplemented and -adequate mice was 11.5 and >14 days post-infection, respectively. Se-deficient macrophages permitted significantly higher intracellular bacterial replication than Se-supplemented macrophages ex vivo, corroborating in vivo observations. Since Francisella replicates in alveolar macrophages during the acute phase of pneumonic infection, we hypothesized that macrophage-specific host selenoproteins may restrict replication and systemic spread of bacteria. F. tularensis infection led to an increased expression of several macrophage selenoproteins, suggesting their key role in limiting bacterial replication. Upon challenge with F. tularensis, mice lacking selenoproteins in macrophages (TrspM) displayed lower survival and increased bacterial burden in the lung and systemic tissues in comparison to WT littermate controls. Furthermore, macrophages from TrspM mice were unable to restrict bacterial replication ex vivo in comparison to macrophages from littermate controls. We herein describe a novel function of host macrophage-specific selenoproteins in restriction of intracellular bacterial replication. These data suggest that host selenoproteins may be considered as novel targets for modulating immune response to control a bacterial infection.

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Selenoproteins mediate T cell immunity through an antioxidant mechanism.

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Selenoproteins mediate T cell immunity through an antioxidant mechanism.

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