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Results for “Immunology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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At least 541 records · Page 30Linked to original sources

bioRxiv2018

HCMV glycoprotein B subunit vaccine efficacy was mediated by non-neutralizing antibody effector functions

Human cytomegalovirus (HCMV) is the most common congenital infection worldwide, frequently causing hearing loss and brain damage in afflicted infants. A vaccine to prevent maternal acquisition of HCMV during pregnancy is necessary to reduce the incidence of infant disease. The glycoprotein B (gB) + MF59 adjuvant subunit vaccine platform is the most successful HCMV vaccine tested to-date, demonstrating approximately 50% efficacy in preventing HCMV acquisition in phase II trials. However, the mechanism of vaccine protection remains unknown. Plasma from 33 gB/MF59 vaccinees at peak immunogenicity was tested for gB epitope specificity as well as neutralizing and non-neutralizing anti-HCMV effector functions, and compared to an HCMV-seropositive cohort. gB/MF59 vaccination elicited IgG responses with gB-binding magnitude and avidity comparable to natural infection. Additionally, IgG subclass distribution was similar with predominant IgG1 and IgG3 responses induced by gB vaccination and HCMV infection. However, vaccine-elicited antibodies exhibited limited neutralization of the autologous virus, negligible neutralization of multiple heterologous strains, and limited binding responses against gB structural motifs targeted by neutralizing antibodies including AD-1, AD-2, and Domain I. Interestingly, vaccinees had high-magnitude IgG responses against AD-3 linear epitopes, demonstrating immunodominance against this non-neutralizing, cytosolic region. Finally, vaccine-elicited IgG robustly bound trimeric, membrane-associated gB on the surface of transfected or HCMV-infected cells and mediated virion phagocytosis, though were poor mediators of NK cell activation. Altogether, these data suggest that non-neutralizing antibody functions, including virion phagocytosis, likely played a role in the observed 50% vaccine-mediated protection against HCMV acquisition.\n\nSignificanceThe CDC estimates that every hour, a child is born in the United States with permanent neurologic disability resulting from human cytomegalovirus (HCMV) infection - more than is caused by Down syndrome, fetal alcohol syndrome, and neural tube defects combined. A maternal vaccine to block transmission of HCMV to the developing fetus is a necessary intervention to prevent these adverse outcomes. The gB/MF59 vaccine is the most successful tested clinically to-date, achieving 50% reduction in HCMV acquisition. This manuscript establishes the function and epitope specificity of the humoral response stimulated by this vaccine that may explain the partial vaccine efficacy. Understanding the mechanism of gB/MF59-elicited protective immune responses will guide rational design and evaluation of the next generation of HCMV vaccines.

immunology↗

bioRxiv2018

Type-2 CD8+ T lymphocytes responsive to PGD2 and LTE4 in severe eosinophilic asthma

The functions and in vivo roles of type-2 CD8+ T cells in humans have not been well defined and this cell type has been largely overlooked in models of disease. We investigated this in the context of severe asthma with persistent airway eosinophilia - a phenotype associated with high exacerbation risk and responsiveness to type-2 cytokine-targeted therapies. In two independent cohorts we show that, in contrast to Th2 cells, type-2 cytokine-secreting CD8+CRTH2+ (Tc2) cells are enriched in blood and airways in severe eosinophilic asthma. Concentrations of prostaglandin D2 (PGD2) and cysteinyl leukotriene E4 (LTE4) are also increased in the airways of the same group of patients. In vitro PGD2 and LTE4 function synergistically to trigger Tc2 cell recruitment and activation in a TCR-independent manner. These lipids regulate diverse genes in Tc2 cells inducing type-2 cytokines and many other pro-inflammatory cytokines and chemokines which could contribute to eosinophilia. These findings are consistent with an important innate-like role for human Tc2 cells in severe eosinophilic asthma and suggest a potential target for therapeutic intervention in this and other diseases.

immunology↗

bioRxiv2018

MAIT cells contribute to protection against lethal influenza infection in vivo

Mucosal associated invariant T (MAIT) cells are evolutionarily-conserved, innate-like lymphocytes which are abundant in human lungs and can contribute to protection against pulmonary bacterial infection. MAIT cells are also activated during human viral infections, yet it remains unknown whether MAIT cells play a significant protective or even detrimental role during viral infections in vivo. Using murine experimental challenge with two strains of influenza A virus, we show that MAIT cells accumulated and were activated early in infection, with upregulation of CD25, CD69 and Granzyme B, peaking at 5 days post infection. Activation was modulated via cytokines independently of MR1. MAIT cell-deficient MR1-/- mice showed enhanced weight loss and mortality to severe (H1N1) influenza. This was ameliorated by prior adoptive transfer of pulmonary MAIT cells in both immunocompetent and immunodeficient RAG2-/-{gamma}C-/- mice. Thus, MAIT cells contribute to protection during respiratory viral infections, and constitute a potential target for therapeutic manipulation.

immunology↗

bioRxiv2018

Highly efficient and versatile plasmid-based gene editing in primary T cells

Adoptive cell transfer (ACT) is an important approach for basic research and emerges as an effective treatment for various diseases including infections and blood cancers. Direct genetic manipulation of primary immune cells opens up unprecedented research opportunities and could be applied to enhance cellular therapeutic products. Here, we report highly efficient genome engineering in primary murine T cells using a plasmid-based RNA-guided CRISPR system. We developed a straightforward approach to ablate genes in up to 90% of cells and to introduce precisely targeted single nucleotide polymorphisms (SNP) in up to 25% of the transfected primary T cells. We used gene editing-mediated allele switching to quantify homology directed repair (HDR), systematically optimize experimental parameters and map a native B cell epitope in primary T cells. Allele switching of a surrogate cell surface marker can be used to enrich cells with successful simultaneous editing of a second gene of interest. Finally, we applied the approach to correct two disease-causing mutations in the Foxp3 gene. Both repairing the cause of the scurfy syndrome, a 2bp insertion in Foxp3, and repairing the clinically relevant Foxp3K276X mutation restored Foxp3 expression in primary T cells.

immunology↗

bioRxiv2018

Analysis of human immunoglobulin VDJ and DJ rearrangements shows N region synthesis by concatenation of cytosine-rich strands preferentially originating from trimmed germline gene segments

The formation of non-templated (N) regions during immunoglobulin gene rearrangement is a major contributor to antibody diversity. To gain insights into the mechanisms behind this, we studied the nucleotide composition of N regions within 29,962 unique human VHDJH-rearrangements and 8,728 unique human DJH-rearrangements containing exactly one identifiable D-gene segment and thus two N regions, N1 and N2. We found a distinct decreasing content of cytosine (C) and increasing content of guanine (G) across each N region, suggesting that N regions are typically generated by concatenation of two 3-overhangs synthesized by addition of nucleoside triphosphates with a preference for dCTP. This challenges the general assumption that the terminal deoxynucleotidyl transferase favors dGTP in vivo. Furthermore, we found that the G and C gradients depended strongly on whether the germline gene segments were trimmed or not. Our data show that C-enriched N addition preferentially happens at trimmed 3-ends of VH-, D-, and JH-gene segments indicating a dependency of the transferase mechanism upon the nuclease mechanism.

immunology↗

bioRxiv2018

Drosophila Toll links systemic immunity to long-term intestinal epithelial integrity

The intestine is an organ where immune and metabolic functions are co-ordinated with tissue renewal via progenitor somatic stem cells (PSSCs). How this is achieved is still unclear. We report that in Drosophila, a generalised infection increased PSSC numbers. This was mimicked by expressing a constitutive form of the immune receptor Toll in PSSCs and blocked when Toll was silenced via RNAi. Without infection, absence of bacterial recognition and downstream Toll signalling resulted in a short lifespan and an age-dependent decrease of PSSCs and gut microbiota. The latter implied a metabolic environment incompatible with the presence of bacteria. Indeed, infection or constitutive Toll signalling in PSSCs triggered 4E-BP transcription in enterocytes, while loss of signalling reduced it. 4E-BP controlled fat levels and sustained the microbiota suggesting that Toll-dependent regulation of 4E-BP was important for long-term gut function. Therefore, the Toll pathway is crucial for responses to both infection and microbiota.

immunology↗

bioRxiv2018

Microbiota-independent antiviral protection conferred by aminoglycoside antibiotics

Antibiotics are widely used to treat infections in humans. However, the impact of antibiotic use on host cells is understudied. We have identified a novel antiviral effect of commonly used aminoglycoside antibiotics. We show that mucosal application of aminoglycosides increased host resistance to a broad range of viral infections including herpes simplex viruses, influenza A virus and Zika virus. Aminoglycoside treatment also reduced viral replication in primary human cells. This antiviral activity was independent of the microbiota as aminoglycoside treatment protected germ-free mice. Microarray analysis uncovered a marked upregulation of transcripts for interferon-stimulated genes (ISGs) following aminoglycoside application. ISG induction was mediated by TLR3, and required TIR-domain-containing adapter-inducing interferon-{beta} (TRIF), signaling adaptor, and interferon regulatory factors 3 (IRF3) and IRF7, transcription factors that promote ISG expression. XCR1+ dendritic cells, which uniquely express TLR3, were recruited to the vaginal mucosa upon aminoglycoside treatment and were required for ISG induction. These results highlight an unexpected ability of aminoglycoside antibiotics to confer broad antiviral resistance in vivo.

immunology↗

bioRxiv2018

A hypermorphic Nfkbid allele represents an Idd7 locus gene contributing to impaired thymic deletion of autoreactive diabetogenic CD8+ T-cells in NOD mice.

In both NOD mice and humans, the development of type 1 diabetes (T1D) is dependent in part on autoreactive CD8+ T-cells recognizing pancreatic {beta}-cell peptides presented by often quite common MHC class I variants. Studies in NOD mice previously revealed the common H2-Kd and/or H2-Db class I molecules expressed by this strain acquire an aberrant ability to mediate pathogenic CD8+ T-cell responses through interactions with T1D susceptibility (Idd) genes outside the MHC. A gene(s) mapping to the Idd7 locus on proximal Chromosome 7 was previously shown to be an important contributor to the failure of the common class I molecules expressed by NOD mice to mediate the normal thymic negative selection of diabetogenic CD8+ T-cells. Using an inducible model of thymic negative selection and mRNA transcript analyses we initially identified an elevated Nfkbid expression variant is likely an NOD Idd7 region gene contributing to impaired thymic deletion of diabetogenic CD8+ T-cells. CRISPR/Cas9-mediated genetic attenuation of Nfkbid expression in NOD mice resulted in improved negative selection of autoreactive diabetogenic AI4 and NY8.3 CD8+ T-cells. These results indicated allelic variants of Nfkbid represent an Idd7 gene contributing to the efficiency of intrathymic deletion of diabetogenic CD8+ T-cells. However, while enhancing thymic deletion of pathogenic CD8+ T-cells, ablation of Nfkbid expression surprisingly accelerated T1D onset in NOD mice likely at least in part by numerically decreasing regulatory T- and B-lymphocytes (Tregs/Bregs), thereby reducing their peripheral immunosuppressive effects.

immunology↗

bioRxiv2018

Therapeutic ICOS blockade reduces T follicular helper cells and improves allergic airway disease

Allergic asthma is a disease of chronic airway inflammation and remodelling, characterised by a dysregulated type 2 response and allergen-specific IgE. T follicular helper cells (TFH) are critical to antibody production and have recently been implicated in allergic airway disease (AAD) pathogenesis. The role of TFH in established disease and the therapeutic potential of targeting them are however not fully understood. Using two aeroallergen driven murine models of chronic AAD, TFH were first identified in the lung draining lymph nodes but with prolonged exposure were present in the lung itself. Sustained allergen exposure led to the accumulation of TFH, and concomitant development of germinal centre B cells. Blockade of Inducible T cell co-stimulator (ICOS) signalling during established AAD depleted TFH without adversely affecting the differentiation of other CD4+ T cell subsets. This resulted in impaired germinal centre responses, reduced allergen specific IgE and ameliorated inflammation and airway hyper-responsiveness, including reduced pulmonary IL-13. TFH did not however appear to produce IL-13 directly, suggesting they indirectly promote type-2 inflammation in the lungs. These data show that TFH play a pivotal role in the regulation of AAD and that targeting the ICOS-L pathway could represent a novel therapeutic approach in this disease.

immunology↗

bioRxiv2018

Endotoxin Tolerance Induced by Different TLR Ligands

Endotoxin tolerance is a long-recognised property of macrophages that leads to an altered response to repeated or chronic exposure to Toll-like receptor (TLR) ligands. The physiological role of tolerance is to limit the potential damage to host tissue that may otherwise result from prolonged production of pro-inflammatory cytokines. Endotoxin tolerance is induced by all TLRs tested to date, however, tolerance induced by the TLR4 ligand lipopolysaccharide (LPS) is by far the best studied. LPS tolerance involves a global transcriptional shift from a pro-inflammatory response toward one characterised by the expression of anti-inflammatory and pro-resolution factors. Although largely reversible, LPS-tolerance leads to a hybrid macrophage activation state that is pro-inflammatory in nature but possesses distinct regulatory anti-inflammatory features. Remarkably, a comparative transcriptomic analysis of tolerance induced by different TLR ligands has not previously been reported. Here we describe the transcriptomic profiles of mouse macrophages tolerised with ligands for TLR2, TLR3, TLR4 and TLR 9. While we identified TLR-specific transcriptional profiles in macrophages tolerised with each ligand, tolerance induced by TLR4 was the most comprehensive state, such that each gene tolerised by any of the TLRs tested was also found to be tolerised by TLR4. Pro-inflammatory cytokines are not universally supressed in all tolerant cells but distinct patterns of cytokine expression distinguished TLR-specific tolerance. Analysis of gene regulatory regions revealed specific DNA sequence motifs associated with distinct states of TLR tolerance, implicating previously identified as well as novel transcriptional regulators of tolerance in macrophages. These data provide a basis for the future exploitation of TLR-specific tolerant states to achieve therapeutic re-programming of the innate immune response.

immunology↗

bioRxiv2018

Pathogenic mycobacteria manipulate host low density lipoprotein metabolism

Changes to lipid metabolism are well-characterised consequences of human tuberculosis infection but their functional relevance are not clearly elucidated in these or other host-mycobacterial systems. The zebrafish-Mycobacterium marinum infection model is used extensively to model many aspects of human-M. tuberculosis pathogenesis but has not been widely used to study the role of infection-induced lipid metabolism. We find mammalian mycobacterial infection-induced alterations in host Low Density Lipoprotein metabolism are conserved in the zebrafish model of mycobacterial pathogenesis. Depletion of LDLR, a key lipid metabolism node, decreased M. marinum burden, and corrected infection-induced altered lipid metabolism resulting in decreased LDL and reduced the rate of macrophage transformation into foam cells. Our results demonstrate a conserved role for infection-induced alterations to host lipid metabolism, and specifically the LDL-LDLR axis, across host-mycobacterial species pairings.\n\nFundingThis work was supported by the Australian National Health and Medical Research Council (APP1099912 and APP1053407 to S.H.O.); Meat and Livestock Australia (P.PSH. 0813 to A.C.P. and K. dS); the Marie Bashir Institute for Infectious Diseases and Biosecurity (grant to S.H.O., A.C.P. and K. dS); the Kenyon Family Foundation Inflammation Award (grant to S.H.O.); the University of Sydney (fellowship to S.H.O.); Conselleria de Economia, Emprego e Industria (GAIN), Xunta de Galicia (grant IN607B 2016/12 to Institute of Marine Research (IIM-CSIC)).

immunology↗

bioRxiv2018

Interaction of septin 7 and DOCK8 in equine lymphocytes reveals novel insights into signaling pathways associated with autoimmunity

The GTP-binding protein septin 7 is involved in various cellular processes, including cytoskeleton organization, migration and the regulation of cell shape. Septin 7 function in lymphocytes, however, is poorly characterized. Since the intracellular signaling role of septin 7 is dependent on its interaction network, interaction proteomics was applied to attain novel knowledge about septin 7 function in hematopoietic cells. Our previous finding of decreased septin 7 expression in blood-derived lymphocytes in ERU, a spontaneous animal model for autoimmune uveitis in man, extended the role of septin 7 to a potential key player in autoimmunity. Here, we revealed novel insights into septin 7 function by identification of DOCK8 as an interaction partner in primary blood-derived lymphocytes. Since DOCK8 is associated with important immune functions, our finding of significantly decreased DOCK8 expression and altered DOCK8 interaction network in ERU might explain changes in immune response and shows the contribution of DOCK8 in pathomechanisms of spontaneous autoimmune diseases. Moreover, our analyses revealed insights in DOCK8 function, by identifying the signal transducer ILK as a DOCK8 interactor in lymphocytes. Our finding of the enhanced enrichment of ILK in ERU cases indicates a deviant influence of DOCK8 on inter- and intracellular signaling in autoimmune disease.

immunology↗

bioRxiv2018

Charcot-Leyden Crystals activate the NLRP3 inflammasome and cause IL-1β inflammation

Charcot-Leyden crystals (CLCs) are Galectin-10 protein crystals that can form after eosinophils degranule. CLCs can appear and persist in tissues from patients with eosinophilic disorders, such as asthma, allergic reactions, fungal, and helminthic infections. Despite abundant reports of their occurrence in human disease, the inflammatory potential of CLCs has remained unknown. Here we show that CLCs induce IL-1{beta} release upon their uptake by primary human macrophages in vitro, and that they induce inflammation in vivo in mouse models of acute peritonitis and bronchitis. CLC-induced IL-1{beta} was dependent on NLRP3 and caspase-1, and their instillation in inflammasome reporter mice promoted the assembly of ASC complexes and IL-1{beta} secretion in the lungs. Our findings reveal that CLCs are recognized by the NLRP3 inflammasome, which may sustain inflammation that follows eosinophilic inflammatory processes.

immunology↗

bioRxiv2018

The Immune Deficiency Pathway Attenuates Insulin Signaling to Protect Against Infection.

Immune and metabolic pathways collectively influence host responses to microbial invaders, and mutations in one pathway frequently disrupt activity in the other. We used the Drosophila model to characterize metabolic homeostasis in flies with modified Immune Deficiency (IMD) pathway activity. The IMD pathway is very similar to the mammalian Tumor Necrosis Factor-alpha pathway, a key regulator of vertebrate immunity and metabolism. We found that persistent activation of IMD resulted in hyperglycemia, depleted fat reserves, and developmental delays, implicating IMD in metabolic regulation. Consistent with this hypothesis, we found that imd mutants weigh more, are hyperlipidemic, and have impaired glucose tolerance. To test the importance of metabolic regulation for host responses to bacterial infection, we challenged insulin pathway mutants with lethal doses of several Drosophila pathogens. We found that loss-of-function mutations in the insulin pathway impacted host responses to infection in a manner that depends on the route of infection, and the identity of the infectious microbe. Combined, our results support a role for coordinated regulation of immune and metabolic pathways in host containment of microbial invaders.

immunology↗

bioRxiv2018

Identification of Variable and Joining germline genes and alleles for Rhesus macaque from B-cell receptor repertoires

The Rhesus macaque is a valuable preclinical animal model to estimate vaccine effectiveness, and is also important for understanding antibody maturation and B-cell repertoire evolution responding to vaccination; however, incomplete mapping of rhesus immunoglobulin germline genes hinders the research efforts. To address this deficiency, we sequenced B-cell receptor (BCR) repertoires of 75 India Rhesus macaques. Using a bioinformatic method that has been validated with BCR repertoire analysis of three human donors, we were able to infer rhesus Variable (V) and Joint(J) germline alleles, identifying a total of 122 V and 20 J germline alleles. Importantly, 91 V and 13 J alleles were novel, and 40 V and 13 J genes were found at a novel genome region that has not been previously recorded. The novelty of these newly identified alleles was supported by two observations. Firstly, 50 V and 5 J novel alleles were observed in whole genome sequencing data of 10 Rhesus macaques. Secondly, using alignment reference including the novel alleles, the mutation rate of rearranged repertoires was significant declined in 9 other irrelevant samples, and all our identified novel V and J alleles were 100% identity mapped by rearranged repertoire data. These newly identified novel alleles, along with previous reported alleles, provide an important reference for future investigations of rhesus immune repertoire evolution, in response to vaccination or infection. In addition, the method outlined in our study offered an example to future efforts in identifying novel immunoglobulin alleles.

immunology↗

bioRxiv2018

Schistosomiasis Induces Persistent DNA Methylation and Tuberculosis-specific Immune Changes

Epigenetic mechanisms, like DNA methylation, determine immune cell phenotype. To understand the epigenetic alterations induced by helminth co-infections, we evaluated the longitudinal effect of ascariasis and schistosomiasis infection on CD4+ T cell DNA methylation and the downstream tuberculosis (TB)-specific and BCG-induced immune phenotype. All experiments were performed on human primary immune cells from a longitudinal cohort of recently TB-exposed children. Compared to age-matched uninfected controls, children with active Schistosoma haematobium and Ascaris lumbricoides infection had 751 differentially DNA methylated genes with 72% hyper-methylated. Gene ontology pathway analysis identified inhibition of IFN-{gamma} signaling, cellular proliferation, and the Th1 pathway. Targeted RT-PCR after methyl-specific endonuclease digestion confirmed DNA hyper-methylation of the transcription factors BATF3, ID2, STAT5A, IRF5, PPARg, RUNX2, IRF4 and NFATC1 and cytokines or cytokine receptors IFNGR1, TNFS11, RELT (TNF receptor), IL12RB2 and IL12B (p< 0.001; Sidak-Bonferroni). Functional blockage of the IFN-{gamma} signaling pathway was confirmed with helminth-infected individuals having decreased up-regulation of IFN-{gamma}-inducible genes (Mann-Whitney p < 0.05). Hypo-methylation of the IL-4 pathway and DNA hyper-methylation of the Th1 pathway was confirmed by antigen-specific multidimensional flow cytometry demonstrating decreased TB-specific IFN-{gamma} and TNF and increased IL-4 production by CD4+ T cells (Wilcoxon signed rank P <0.05). In S.haematobium infected individuals, these DNA methylation and immune phenotypic changes persisted at least six months after successful deworming. This work demonstrates that helminth infection induces DNA methylation and immune perturbations that inhibit TB-specific immune control and that the duration of these changes are helminth-specific.

immunology↗

bioRxiv2018

Is IκBζ constitutively expressed in mammalian airway epithelium?

I{kappa}B{zeta} is a transcriptional factor induced primarily in immune cells upon Toll-like receptor (TLR) activation that drives important cytokine responses. Recent studies have demonstrated constitutive I{kappa}B{zeta} expression in the epithelial cells of mouse skin and eyes, possibly reflecting the activation of TLRs by pathogen-associated molecular patterns (PAMPs). In this context, another mucosal surface, the lung epithelium, may not be as actively exposed to the external environment as the skin and the conjunctiva, especially since the lower lung airways are typically conceived to be sterile. Whether I{kappa}B{zeta} expression in the lungs is constitutive or induced remains largely unexplored. This is especially important since I{kappa}B{zeta} has been shown to promote the expression of protective cytokine and antimicrobial peptide responses, supporting a role for I{kappa}B{zeta} in lung host defense. We hence evaluated I{kappa}B{zeta} expression in airway epithelia of both humans and mice using immunostaining with antiserum raised against recombinant I{kappa}B{zeta} in our laboratory. We observed positive signal in the nuclei of ciliated epithelial cells lining the central airways. Airway cells of gnotobiotic mice also stained positive, suggesting that I{kappa}B{zeta} expression does not require induction by bacterial PAMPs. Unexpectedly, we also observed staining in the lung epithelia of I{kappa}B{zeta} knockout mice, indicating possible false positive signals from our immunohistochemistry experiments. In this context, 2D gel analysis followed by mass spectrometry revealed that our I{kappa}B{zeta} antiserum also detected a nuclear protein lamin B1. Nevertheless, immunoblotting tissue homogenates from gnotobiotic mouse lungs and primary human airway epithelial cells showed the appropriate 86 kDa band for I{kappa}B{zeta}. Together, these results demonstrate constitutive I{kappa}B{zeta} expression in airway epithelium, suggesting that lung epithelial cells may depend upon I{kappa}B{zeta} expression for airway protection.

immunology↗

bioRxiv2018

Gut bacterial metabolite Urolithin A (UA) mitigates Ca2+ 1 entry inT cells by regulating miR-10a-5p

The gut microbiota influences several biological functions including immune response. Inflammatory bowel disease is favourably influenced by consumption of several dietary natural plant products such as pomegranate, walnuts and berries containing polyphenolic compounds such as ellagitannins and ellagic acid. The gut microbiota metabolises ellagic acid leading to formation of bioactive urolithins A, B, C and D. Urolithin A (UA) is the most active and effective gut metabolite and acts as a potent anti-inflammatory and anti-oxidant agent. However, how gut metabolite UA affects the function of immune cells remained incompletely understood. T cell proliferation is stimulated by store operated Ca2+ entry (SOCE) resulting from stimulation of Orai1 by STIM1/STIM2. We show here that treatment of murine CD4+ T cells with UA (10 {micro}M, 3 days) significantly blunted SOCE in CD4+ T cells, an effect paralleled by significant downregulation of Orai1 and STIM1/2 transcript levels and protein abundance. UA treatment further increased miR-10a-5p abundance in CD4+ T cells in a dose dependent fashion. Overexpression of miR-10a-5p significantly decreased STIM1/2 and Orai1 mRNA and protein levels as well as SOCE in CD4+ T cells. UA further decreased CD4+ T cell proliferation. Thus, bacterial metabolite UA up-regulates miR-10a-5p thus interfering with Orai1/STIM1/STIM2 expression, store operated Ca2+ entry and proliferation of murine CD4+ T cells.

immunology↗