ORCID Profile
0000-0003-1721-8922
Current Organisation
University of Queensland
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Cellular Immunology | Humoural Immunology and Immunochemistry | Immunology | Biochemistry and Cell Biology not elsewhere classified | Tumour Immunology
Publisher: Wiley
Date: 03-04-2009
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.INTIMP.2015.03.046
Abstract: The adaptive immune system, composed of lymphocytes, recognizes ersified antigens and generates immunological memory. According to the canonical model, it is the innate immune system that captures pathogens and senses environment to activate adaptive lymphocytes through antigen presentation, costimulatory signals and cytokine milieu. Emerging evidence indicates that environmental cues can be directly conveyed to lymphocytes by the aryl hydrocarbon receptor (AhR). AhR is a ligand-activated transcription factor that widely expresses in many immune cell lineages and recognizes a broad range of ligands including endogenous and dietary metabolites, microbial derivatives and xenobiotics. This review will focus on the regulatory role of AhR in not only adaptive but also innate lymphocytes including recently discovered innate lymphoid cells.
Publisher: Frontiers Media SA
Date: 04-06-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2018
DOI: 10.1097/ACI.0000000000000480
Abstract: The discovery of novel T-cell subsets including follicular helper T (Tfh) cells has broadened our knowledge on the complex immune networks in allergic diseases. This review summarizes the evidence for Tfh cells in controlling immune responses to allergens with a particular focus on immunoglobulin E (IgE) production and discusses the implication of such regulation in allergen-specific immunotherapy. Tfh cells support the production of IgE in animal models for allergic diseases. Among Tfh cells, the type 2 subset (Tfh2) is considered as the major player that secretes IL-4 and promotes the isotype switching to IgE. In human inflammatory airway diseases, including allergic rhinitis, asthma, and nasal polyps, the increased frequencies of circulating or tissue Tfh2 cells have been reported. Notably, the frequencies of Dermatophagoides pteronyssinus group 1 (Der p 1)-specific IL-4 + Tfh cells in blood positively correlated with serum Der p-specific IgE levels in allergic rhinitis patients. After allergen immunotherapy (AIT), Der p 1-specific IL-4 + Tfh cells declined in allergic rhinitis patients, which associated with the remission of clinical symptoms. Allergen-specific IL-4 + Tfh cells contribute to the production of allergen-specific IgE and correlate with clinical efficacy of AIT in allergic rhinitis patients, which suggest allergen-specific Tfh cells as a promising therapeutic target and biomarker for AIT in allergic rhinitis.
Publisher: Cold Spring Harbor Laboratory
Date: 14-01-2021
DOI: 10.1101/2021.01.12.426467
Abstract: Transcriptome profiling and differential gene expression constitute a ubiquitous tool in biomedical research and clinical application. Linear dimensionality reduction methods especially principal component analysis (PCA) are widely used in detecting s le-to-s le heterogeneity in bulk transcriptomic datasets so that appropriate analytic methods can be used to correct batch effects, remove outliers and distinguish subgroups. In response to the challenge in analysing transcriptomic datasets with large s le size such as single-cell RNA-sequencing (scRNA-seq), non-linear dimensionality reduction methods were developed. t-distributed stochastic neighbour embedding (t-SNE) and uniform manifold approximation and projection (UMAP) show the advantage of preserving local information among s les and enable effective identification of heterogeneity and efficient organisation of clusters in scRNA-seq analysis. However, the utility of t-SNE and UMAP in bulk transcriptomic analysis has not been carefully examined. Therefore, we compared major dimensionality reduction methods (linear: PCA nonlinear: multidimensional scaling (MDS), t-SNE, and UMAP) in analysing 71 bulk transcriptomic datasets with large s le sizes. UMAP was found superior in preserving s le level neighbourhood information and maintaining clustering accuracy, thus conspicuously differentiating batch effects, identifying pre-defined biological groups and revealing in-depth clustering structures. We further verified that new clustering structures visualised by UMAP were associated with biological features and clinical meaning. Therefore, we recommend the adoption of UMAP in visualising and analysing of sizable bulk transcriptomic datasets.
Publisher: Springer Science and Business Media LLC
Date: 13-12-2017
DOI: 10.1038/S41598-017-16085-Y
Abstract: Most lung cancers are diagnosed at fairly advanced stages due to limited clinical symptoms. Platinum-based chemotherapy, either as single regimen or in combination with radiation, is one of the major recommendations for the patients. Earlier evaluation of the effectiveness of the chemotherapies is critical for developing better treatment plan given the toxicity of the chemotherapeutic reagents. Drug efficacy could be reflected in the systemic metabolism characteristics though knowledge about which remains scarce. In this study, serum metabolism influence of three types of commonly used platinum-based combination chemotherapy regimens, namely cisplatin with gemcitabine, vinorelbine or docetaxel, were studied using pattern recognition coupled with nuclear magnetic resonance techniques. The treated patients were ided into sensitive or insensitive subgroups according to their response to the treatments. We found that insensitive subjects can be identified from the sensitive ones with up-regulation of glucose and taurine but reduced alanine and lactate concentrations in serum. The combination chemotherapy of lung cancer is accompanied by disturbances of multiple metabolic pathways such as energy metabolism, phosphatidylcholine biosynthesis, so that the treated patients were marginally discriminated from the untreated. Serum metabolic profile of patients shows potential as an indicator of their response to platinum-based combination chemotherapy.
Publisher: Frontiers Media SA
Date: 31-08-2021
DOI: 10.3389/FPHAR.2021.726035
Abstract: Atopic dermatitis (AD), also known as atopic eczema, is one of the most common skin diseases and is characterized by allergic skin inflammation, redness, and itchiness and is associated with a hyperactivated type 2 immune response. The leading causes of AD include an imbalance in the immune system, genetic predisposition, or environmental factors, making the development of effective pharmacotherapies complex. Steroids are widely used to treat AD however, they provide limited efficacy in the long term and can lead to adverse effects. Thus, novel treatments that offer durable efficacy and fewer side effects are urgently needed. Here, we investigated the therapeutic potential of Huangbai Liniment (HB), a traditional Chinese medicine, using an experimental AD mouse model, following our clinical observations of AD patients. In both AD patient and the mouse disease model, HB significantly improved the disease condition. Specifically, patients who received HB treatment on local skin lesions (3–4 times/day) showed improved resolution of inflammation. Using the 1-Chloro-2,4-dinitrobenzene (DNCB)-induced AD model in BALB/c mice, we observed that HB profoundly alleviated severe skin inflammation and relieved the itching. The dermatopathological results showed markedly reversed skin inflammation with decreased epidermal thickness and overall cellularity. Correspondingly, HB treatment largely decreased the mRNA expression of proinflammatory cytokines, including IL-1β, TNF-α, IL-17, IL-4, and IL-13, associated with declined gene expression of IL-33, ST2, and GATA3, which are connected to the type 2 immune response. In addition, HB restored immune tolerance by promoting regulatory T (T REG ) cells and inhibiting the generation of T H 1, T H 2, and T H 17 cells in vitro and in the DNCB-induced AD mouse model. For the first time, we demonstrate that HB markedly mitigates skin inflammation in AD patients and the DNCB-induced AD mouse model by reinvigorating the T cell immune balance, shedding light on the future development and application of novel HB-based therapeutics for AD.
Publisher: Elsevier BV
Date: 12-2015
Abstract: Three recent studies provide new insight into the mechanisms that promote the differentiation of antigen-primed T cells into the follicular helper T (Tfh) lineage, revealing a key role for the transcription factor TCF-1 in the regulation of the Bcl6-Blimp-1 axis that mediates the ergence between the Tfh and the Th1 lineages.
Publisher: MDPI AG
Date: 20-03-2018
DOI: 10.3390/IJMS19030916
Publisher: Wiley
Date: 05-11-2014
DOI: 10.1038/ICB.2013.68
Abstract: The generation of immunological memory during an immune response is a hallmark of the adaptive immune system. Follicular helper T (Tfh) cells are a CD4(+) T-cell subset specialised to regulate antibody response. Emerging evidence suggests that during antibody response, Tfh memory is generated along with the generation of B-cell memory. There are multiple layers for the differentiation and function of memory Tfh cells. Both early committed precursor Tfh cells and effector Tfh cells exiting germinal centres can contribute to the memory Tfh pool. Functionally, memory Tfh cells not only enhance a secondary response upon antigen rechallenge but also circulate to non-draining lymph tissues to differentiate into effector Tfh cells in the face of systemic antigen athogen spreading, thus also promoting a primary response. Circulating memory Tfh cells are a valuable marker to monitor the Tfh programme in human autoimmune diseases, infections and vaccinations. Future studies are required to understand the molecular mechanisms determining the commitment and plasticity of Tfh memory and hence the physiological functions of Tfh memory.
Publisher: Wiley
Date: 09-2021
DOI: 10.1002/RAI2.12010
Abstract: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by extraordinary heterogeneity, due to the complex pathogenesis and erse manifestations. Stratification of patients for therapy and prognosis represents a major challenge to manage SLE. Conventional biomarkers for disease diagnosis and activity assessment provide very limited insight into immunological pathogenesis and therapeutic response rates. The advancement of “omics” technologies including genomics, transcriptomics, proteomics, and metabolomics has constituted an unprecedented opportunity to characterize the immunopathological landscape in in idual patients with SLE. Indeed, genomic studies reveal a subset of SLE patients carrying one or more functional single nucleotide polymorphisms (SNPs) underlying immune dysregulation while transcriptomic studies have revealed subgroups in SLE patients showing distinct signatures for Type I interferon (TI‐IFN) pathway activation or aberrant differentiation of B cells into plasma cells. This review will summarize results from the latest studies using omics technology to understand SLE heterogeneity. In addition, we propose that the application of artificial intelligence, such as by machine learning‐based nonlinear dimensionality reduction method uniform manifold approximation and projection (UMAP) can further strengthen the analysis of omics big data. The combination of new technology and novel analysis pipeline can lead to breakthroughs in stratifying SLE patients for a better monitoring of disease activity and more precise design of treatment regime, not only for conventional immunosuppression but also novel immunotherapies targeting B‐cell activating factor (BAFF), TI‐IFN, and interleukin 2 (IL‐2).
Publisher: Wiley
Date: 2021
DOI: 10.1002/CTI2.1251
Publisher: Frontiers Media SA
Date: 22-08-2019
Publisher: Springer Science and Business Media LLC
Date: 02-2008
DOI: 10.1038/NATURE06729
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-01-2014
Publisher: BMJ
Date: 19-09-2019
DOI: 10.1136/ANNRHEUMDIS-2019-215396
Abstract: Open-labelled clinical trials suggested that low-dose IL-2 might be effective in treatment of systemic lupus erythematosus (SLE). A double-blind and placebo-controlled trial is required to formally evaluate the safety and efficacy of low-dose IL-2 therapy. A randomised, double-blind and placebo-controlled clinical trial was designed to treat 60 patients with active SLE. These patients received either IL-2 (n=30) or placebo (n=30) with standard treatment for 12 weeks, and were followed up for additional 12 weeks. IL-2 at a dose of 1 million IU or placebo was administered subcutaneously every other day for 2 weeks and followed by a 2-week break as one treatment cycle. The primary endpoint was the SLE Responder Index-4 (SRI-4) at week 12. The secondary endpoints were other clinical responses, safety and dynamics of immune cell subsets. At week 12, the SRI-4 response rates were 55.17% and 30.00% for IL-2 and placebo, respectively (p=0.052). At week 24, the SRI-4 response rate of IL-2 group was 65.52%, compared with 36.67% of the placebo group (p=0.027). The primary endpoint was not met at week 12. Low-dose IL-2 treatment resulted in 53.85% (7/13) complete remission in patients with lupus nephritis, compared with 16.67% (2/12) in the placebo group (p=0.036). No serious infection was observed in the IL-2 group, but two in placebo group. Besides expansion of regulatory T cells, low-dose IL-2 may also sustain cellular immunity with enhanced natural killer cells. Low-dose IL-2 might be effective and tolerated in treatment of SLE. ClinicalTrials.gov Registries ( NCT02465580 and NCT02932137 ).
Publisher: Elsevier BV
Date: 07-2021
DOI: 10.1016/J.CELREP.2021.109442
Abstract: Transcriptomic analysis plays a key role in biomedical research. Linear dimensionality reduction methods, especially principal-component analysis (PCA), are widely used in detecting s le-to-s le heterogeneity, while recently developed non-linear methods, such as t-distributed stochastic neighbor embedding (t-SNE) and uniform manifold approximation and projection (UMAP), can efficiently cluster heterogeneous s les in single-cell RNA sequencing analysis. Yet, the application of t-SNE and UMAP in bulk transcriptomic analysis and comparison with conventional methods have not been achieved. We compare four major dimensionality reduction methods (PCA, multidimensional scaling [MDS], t-SNE, and UMAP) in analyzing 71 large bulk transcriptomic datasets. UMAP is superior to PCA and MDS but shows some advantages over t-SNE in differentiating batch effects, identifying pre-defined biological groups, and revealing in-depth clusters in two-dimensional space. Importantly, UMAP generates s le clusters uncovering biological features and clinical meaning. We recommend deploying UMAP in visualizing and analyzing sizable bulk transcriptomic datasets to reinforce s le heterogeneity analysis.
Publisher: The American Association of Immunologists
Date: 15-11-2014
Abstract: The dynamic interplay between regulatory T cells (Tregs) and effector T cells (Teffs) governs the balance between tolerance and effector immune responses. Perturbations of Treg frequency and function or imbalances in Treg/Teff levels are associated with the development of autoimmunity. The factors that mediate these changes remain poorly understood and were investigated in this study in murine autoimmune arthritis. Tregs displayed a stable phenotype in arthritic mice and were fully functional in in vitro suppression assays. However, their expansion was delayed relative to Teffs (T follicular helper cells and Th17 cells) during the early stages of autoimmune reactivity. This imbalance is likely to have led to insufficient Treg control of Teffs and induced autoimmunity. Moreover, a counterregulatory and probably IL-7–driven increase in thymic Treg production and recruitment to inflamed tissues was too slow for disease prevention. Increased Teff over Treg expansion was further aggravated by inflammation and lymphopenia. Both these conditions contribute to autoimmune pathogenesis and were accompanied by decreases in the availability of IL-2 and increases in levels of IL-21. IL-2 neutralization or supplementation was used to show that Treg expansion mainly depended on this cytokine. IL-21R−/− cells were used to demonstrate that IL-21 promoted the maintenance of Teffs. Thus, at inflammatory sites in experimental arthritis, a deficit in IL-2 h ers Treg proliferation, whereas exaggerated IL-21 levels overwhelm Treg control by supporting Teff expansion. This identifies IL-2 and IL-21 as targets for manipulation in therapies for autoimmunity.
Publisher: Wiley
Date: 09-2008
DOI: 10.1111/J.1445-5994.2008.01719.X
Abstract: Several important physiological and maturational changes occur in sleep development during the paediatric age range, particularly during infancy and in early childhood. As the pathology of sleep apnoea is superimposed onto a developing and often plastic physiological system, children often show a different pathophysiology to their adult counterparts. These factors need to be incorporated into the evaluation of a child's sleep problems. Particular attention should be paid to the developmental stage of the child. Investigation, interpretation and subsequent management provide further unique challenges and during successive reviews predicted normal changes must also be taken into account. This review article discusses the important physiological and maturational changes that occur in sleep during childhood, some common paediatric sleep conditions and their presentation and the appropriate evaluation and management of these conditions. In the course of the discussion, we have stressed important differences between paediatric and adult sleep medicine.
Publisher: Cold Spring Harbor Laboratory
Date: 31-07-2022
DOI: 10.1101/2022.07.31.502219
Abstract: A defining feature of successful vaccination is the ability to induce long-lived antigen- specific memory cells. Follicular helper T (Tfh) cells specialize in providing help to B cells in mounting protective humoral immunity in infection and after vaccination. Memory Tfh cells that retain the CXCR5 expression can confer protection through enhancing humoral response upon antigen re-exposure but how they are maintained is poorly understood. CXCR5 + memory Tfh cells in human blood are ided into Tfh1, Tfh2 and Tfh17 cells by the expression of chemokine receptors CXCR3 and CCR6 associated with Th1 and Th17 respectively. Here, we developed a new method to induce Tfh1, Tfh2 and Tfh17-like (iTfh1, iTfh2 and iTfh17) cells in vitro . Although all three iTfh subsets efficiently support antibody responses in recipient mice with immediate immunization, iTfh17 cells are superior to iTfh1 and iTfh2 cells in supporting antibody response to a later immunization after extended resting in vivo to mimic memory maintenance. Notably, the counterpart human Tfh17 cells are selectively enriched in CCR7 + central memory Tfh (Tfh CM ) with survival and proliferative advantages. Furthermore, the analysis of multiple human cohorts that received different vaccines for HBV, influenza virus, tetanus toxin or measles revealed that vaccine-specific Tfh17 cells outcompete Tfh1 or Tfh2 cells for the persistence in memory phase. Therefore, the complementary mouse and human results showing the advantage of Tfh17 cells in maintenance and memory function supports the notion that Tfh17-induced immunization might be preferable in vaccine development to confer long-term protection.
Publisher: Wiley
Date: 28-03-2016
DOI: 10.1002/ART.39481
Publisher: Elsevier BV
Date: 07-2018
Publisher: Springer Science and Business Media LLC
Date: 11-05-2017
Publisher: Springer Science and Business Media LLC
Date: 05-2021
DOI: 10.1186/S12886-021-01951-1
Abstract: The purpose of this study is to investigate the aqueous humor (AH) T lymphocyte subsets and cytokines of acute retinal necrosis (ARN) to elucidate the immunologic inflammatory features of this disorder. Three patients with ARN infected with varicella zoster virus (VZV) who underwent multiple intravitreal injections of ganciclovir were enrolled in this study. The control group consisted of four non-infectious patients with acute anterior uveitis (AAU). Flow cytometric analysis was performed on the lymphocyte subsets from the AH and peripheral blood (PB) s les during the active phase of intraocular inflammation. Five inflammatory cytokines were measured in each AH s le and various clinical characteristics were also assessed. VZV deoxyribonucleic acid (DNA) was detected by real-time polymerase chain reaction (PCR) in AH from all the ARN patients, who showed higher CD8+ T lymphocytes population in AH than the AAU patients ( p = 0.006). CD4/CD8 ratios of T lymphocytes and the percentage of CD8 + CD25+ T lymphocytes in AH were significantly lower in ARN than in AAU ( p = 0.006 p = 0.012). In the ARN patients, the percentages of CD4+ and CD8+ T lymphocytes in AH were higher than those found in PB. The percentage of CD4 + CD25+ T lymphocytes in AH was significantly higher than the proportion in PB in the AAU patients ( p = 0.001). Immunoregulatory cytokine Interleukin-10 in AH was significantly elevated in the ARN patients in comparison with the case of the AAU patients ( p = 0.036). In ARN, the copy number of VZV DNA in AH positively correlated with the percentage of CD8+ T lymphocytes in AH and negatively correlated with the CD4/CD8 ratio in AH during the course of disease treatment ( p = 0.009, r = 0.92 p = 0.039, r = − 0.834). The ARN patients caused by VZV had different intraocular T lymphocyte subsets and cytokines profile than those of the non-infectious patients. High percentages of CD8+ T lymphocytes and low CD4/CD8 T cell ratios may be a potential biomarker for diagnosis of viral-infectious uveitis. T lymphocytes examination at the inflammatory sites has the potential to become a useful research tool for differentiating viral and non-viral uveitis.
Publisher: eLife Sciences Publications, Ltd
Date: 17-12-2022
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.IMMUNI.2013.01.011
Abstract: Accumulation of T follicular helper (Tfh) cells and proinflammatory cytokines drive autoantibody-mediated diseases. The RNA-binding protein Roquin-1 (Rc3h1) represses the inducible costimulator ICOS and interferon-γ (IFN-γ) in T cells to prevent Tfh cell accumulation. Unlike Rc3h1(san) mice with a mutation in the ROQ domain of Roquin-1, mice lacking the protein, paradoxically do not display increased Tfh cells. Here we have analyzed mice with mutations that eliminate the RING domain from Roquin-1 or its paralog, Roquin-2 (Rc3h2). RING or ROQ mutations both disrupted Icos mRNA regulation by Roquin-1, but, unlike the ROQ mutant that still occupied mRNA-regulating stress granules, RING-deficient Roquin-1 failed to localize to stress granules and allowed Roquin-2 to compensate in the repression of ICOS and Tfh cells. These paralogs also targeted tumor necrosis factor (TNF) in nonlymphoid cells, ameliorating autoantibody-induced arthritis. The Roquin family emerges as a posttranscriptional brake in the adaptive and innate phases of antibody responses.
Publisher: Springer Science and Business Media LLC
Date: 13-01-2015
Abstract: Advances in our understanding of the pathogenesis of primary Sjögren syndrome (pSS) characterize it as a highly complex process encompassing both the initiation of innate immunity and subsequent adaptive immune responses. IL-21 is receiving attention as a potential key player in the pathogenesis of pSS owing to its pleiotropic effects on the type I interferon signalling pathway, and newly identified roles in generation of follicular and IL-17-producing subtypes of helper T cells, as well as plasma-cell differentiation and B-cell activation. Taking into consideration the erse biological functions of IL-21 and its clinical relevance to pSS, we propose that this cytokine has a central role in orchestrating the complex immune response in pSS. This hypothesis might provide new insight into the pathogenesis of pSS and facilitate the development of effective therapeutic strategies.
Publisher: Wiley
Date: 16-10-2008
Abstract: Selection of B cells subjected to hypermutation in germinal centres (GC) during T cell-dependent (TD) antibody responses yields memory cells and long-lived plasma cells that produce high affinity antibodies biased to foreign antigens rather than self-antigens. GC also form in T-independent (TI) responses to polysaccharide antigens but failed selection results in GC involution and memory cells are not generated. To date there are no markers that allow phenotypic distinction of T-dependent and TI germinal centre B cells. We compared the global gene expression of GC B cells purified from mice immunized with either TD or TI antigens and identified eighty genes that are differentially expressed in TD GC. Significantly, the largest cluster comprises genes involved in growth and guidance of neuron axons such as Plexin B2, Basp1, Nelf, Shh, Sc4mol and Sult4alpha. This is consistent with formation of long neurite (axon and dendrite)-like structures by mouse and human GC B cells, which may facilitate T:B cell interactions within GC, affinity maturation and B cell memory formation. Expression of BASP1 and PLEXIN B2 protein is very low or undetectable in resting and TI GC B cells, but markedly upregulated in GC B cells induced in the presence of T cell help. Finally we show some of the axon growth genes upregulated in TD-GC B cells including Basp1, Shh, Sult4alpha, Sc4mol are also preferentially expressed in post-GC B cell neoplasms.
Publisher: Wiley
Date: 31-05-2008
DOI: 10.1002/ART.23489
Abstract: Although heparanase is recognized as a proangiogenic factor, the involvement of heparanase in rheumatoid arthritis (RA) is unclear. In this study, we assessed heparanase activity in synovial fluid (SF) and synovial tissue (ST) from patients with RA or osteoarthritis (OA), and analyzed the expression of angiogenic pathway-focused genes in ST from RA and OA patients. SF and ST were obtained from the knees of patients with either RA or OA and from asymptomatic donors with no documented history of degenerative or inflammatory joint diseases. Heparanase activity was determined by an enzymatic assay using a radiolabeled substrate, and the presence of heparanase in ST was demonstrated by Western blotting. The expression of angiogenesis genes, including heparanase, in ST was analyzed by real-time quantitative polymerase chain reaction. Heparanase activity was dramatically higher (>100-fold) in SF and ST from RA patients than in SF and ST from OA patients and asymptomatic donors. Active heparanase enzyme was detected and heparanase messenger RNA was up-regulated in ST from RA patients. We also found that angiogenesis gene expression was significantly regulated in RA synovium, and was correlated with heparanase activity. These findings are novel and contribute to our understanding of joint destruction in RA, suggesting that heparanase may be a reliable prognostic factor for RA progression and an attractive target for the treatment of RA.
Publisher: Frontiers Media SA
Date: 09-08-2019
Publisher: MDPI AG
Date: 23-12-2020
DOI: 10.3390/IJMS22010057
Abstract: The immune privilege of the testes is necessary to prevent immune attacks to gamete-specific antigens and paternal major histocompatibility complex (MHC) antigens, allowing for normal spermatogenesis. However, infection and inflammation of the male genital tract can break the immune tolerance and represent a significant cause of male infertility. Different T cell subsets have been identified in mammalian testes, which may be involved in the maintenance of immune tolerance and pathogenic immune responses in testicular infection and inflammation. We reviewed the evidence in the published literature on different T subtypes (regulatory T cells, helper T cells, cytotoxic T cells, γδ T cells, and natural killer T cells) in human and animal testes that support their regulatory roles in infertility and the orchitis pathology. While many in vitro studies have indicated the regulation potential of functional T cell subsets and their possible interaction with Sertoli cells, Leydig cells, and spermatogenesis, both under physiological and pathological processes, there have been no in situ studies to date. Nevertheless, the normal distribution and function of T cell subsets are essential for the immune privilege of the testes and intact spermatogenesis, and T cell-mediated immune response drives testicular inflammation. The distinct function of different T cell subsets in testicular homeostasis and the orchitis pathology suggests a considerable potential of targeting specific T cell subsets for therapies targeting chronic orchitis and immune infertility.
Publisher: Research Square Platform LLC
Date: 07-06-2023
DOI: 10.21203/RS.3.RS-3001427/V1
Abstract: New-onset HLA-DR-associated anti-citrullinated protein autoantibody (ACPA) + rheumatoid arthritis (RA) synovial tissue (ST) contains highly-expanded TCR-αβ clonotypes, some viral-antigen-reactive. However, it is unknown how viral-specific T-cells sustain ACPA + RA. We studied paired peripheral blood (PB) and ST TCR repertoires in drug-naïve ACPA + HLA-DRB1*04:01 + diffuse-myeloid RA ST pathology. To model effects of viral infection, we induced ovalbumin antigen-induced arthritis (AIA) in mice with latent murine-cytomegalovirus or recovered from acute lymphocytic-choriomeningitis virus. We show that most clonally-expanded CD8 + T cells had polyfunctional TNF + IFNγ + cytotoxic T-lymphocyte (CTL) signatures. Transcriptomic profiles of ST CD4 + T-cell clonotypes were Th2-like and IL-6-signaled central memory-like. CMV-specific tetramers confirmed in-silico prediction of viral-epitope recognition by CTL. Perivascular GZMB + CD8 + T cells co-localized with CD4 + T-cells, dendritic cells, fibroblasts and IL-6. After viral infection, AIA severity increased with enhanced viral and ovalbumin-specific TNF + IFN-γ + T-cell cytokines, suggesting that in the diffuse-myeloid rheumatoid-synovial perivascular niche, polyfunctional bystander-CTL reinforce myeloid- and CD4 + T-cell activation.
Publisher: Springer Science and Business Media LLC
Date: 05-2005
DOI: 10.1038/NATURE03555
Abstract: Despite the sequencing of the human and mouse genomes, few genetic mechanisms for protecting against autoimmune disease are currently known. Here we systematically screen the mouse genome for autoimmune regulators to isolate a mouse strain, sanroque, with severe autoimmune disease resulting from a single recessive defect in a previously unknown mechanism for repressing antibody responses to self. The sanroque mutation acts within mature T cells to cause formation of excessive numbers of follicular helper T cells and germinal centres. The mutation disrupts a repressor of ICOS, an essential co-stimulatory receptor for follicular T cells, and results in excessive production of the cytokine interleukin-21. sanroque mice fail to repress diabetes-causing T cells, and develop high titres of autoantibodies and a pattern of pathology consistent with lupus. The causative mutation is in a gene of previously unknown function, roquin (Rc3h1), which encodes a highly conserved member of the RING-type ubiquitin ligase protein family. The Roquin protein is distinguished by the presence of a CCCH zinc-finger found in RNA-binding proteins, and localization to cytosolic RNA granules implicated in regulating messenger RNA translation and stability.
Publisher: Elsevier BV
Date: 06-2023
Publisher: Wiley
Date: 15-12-2009
DOI: 10.1111/J.1440-1681.2009.05269.X
Abstract: 1. Evidence gathered in recent years has revealed microRNAs (miRNAs) fine-tune gene expression and play an important role in various cellular processes, including cell growth, differentiation, proliferation and apoptosis. 2. The present review summarizes current knowledge of miRNA pathways in the pathogenesis of cancer, cardiac diseases, neurodegenerative diseases, diabetes, autoimmune/inflammatory diseases and infection. 3. There is considerable potential to target miRNAs as a novel approach in the treatment of human diseases. Currently, miRNA-based therapies are being examined in both animal models and human clinical trials.
Publisher: Wiley
Date: 14-04-2020
DOI: 10.1111/ALL.14288
Abstract: The contribution of B‐cell subsets and T‐B cell interaction to the pathogenesis of allergic rhinitis (AR) and mechanisms of allergen immunotherapy (AIT) remain poorly understood. This study aimed to outline circulating B‐cell signature, the underlying mechanism, and its association with clinical response to AIT in patients with AR. IgD/CD27 and CD24/CD38 core gating systems were used to determine frequencies and phenotypes of B cells. Correlations between B cells, T cells, antigen‐specific IgE, and disease severity in AR patients were investigated. Switched memory B cells were co‐cultured with type 2 follicular helper T (Tfh2) cells and follicular regulatory T (Tfr) cells. Associations between B‐cell subsets and clinical benefits of AIT were analyzed. Frequencies and absolute numbers of circulating memory B cells were increased in AR patients. CD23 expression on CD19 + CD20 + CD27 + IgD − switched memory B cells was significantly enhanced and positively correlated with antigen‐specific IgE levels, symptom scores, and Tfh2/Tfr cell ratio in AR patients. Compared with those from healthy controls, Tfh2 cells from AR patients had a greater capacity to induce CD23 expression on switched memory B cells via IL‐4, which was unable to be sufficiently suppressed by AR‐associated Tfr cells with defective IL‐10 expression. CD23 expression on switched memory B cells was downregulated after 12‐month AIT, which positively associated with disease remission in AR patients. T‐B cell interaction, bridged by CD23 expression particularly on switched memory B cells, may be involved in the disease pathogenesis and mechanism of AIT in patients with AR.
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1016/J.IMMUNI.2014.10.003
Abstract: MicroRNA (miR)-146a-deficient mice develop low-grade, chronic, and systemic inflammation, similar to inflammaging. Hu et al. (2014) demonstrate that the lack of miR-155 prevents the accumulation of Tfh cells and inflammaging in miR-146a-deficient mice. They identify Fosl2 as a functionally important target of miR-155 in Tfh cells.
Publisher: Elsevier BV
Date: 07-2008
DOI: 10.1016/J.IMMUNI.2008.06.001
Abstract: T cell help to B cells is a fundamental property of adaptive immunity, yet only recently have many of the cellular and molecular mechanisms of T cell help emerged. T follicular helper (Tfh) cells are the CD4(+) T helper cells that provide cognate help to B cells for high-affinity antibody production in germinal centers (GC). Tfh cells produce interleukin-21 (IL-21), and we show that IL-21 was necessary for GC formation. However, the central role of IL-21 in GC formation reflected its effects on Tfh cell generation rather than on B cells. Expression of the inducible costimulator (ICOS) was necessary for optimal production of IL-21, indicative of interplay between these two Tfh cell-expressed molecules. Finally, we demonstrate that IL-21's costimulatory capacity for T helper cell differentiation operated at the level of the T cell receptor signalosome through Vav1, a signaling molecule that controls T cell helper function. This study reveals a previously unappreciated role for Tfh cells in the formation of the GC and isotype switching through a CD4(+) T cell-intrinsic requirement for IL-21.
Publisher: The American Association of Immunologists
Date: 07-2021
Abstract: pH sensing by GPR65 regulates various inflammatory conditions, but its role in skin remains unknown. In this study, we performed a phenome-wide association study and report that the T allele of GPR65-intronic single-nucleotide polymorphism rs8005161, which reduces GPR65 signaling, showed a significant association with atopic dermatitis, in addition to inflammatory bowel diseases and asthma, as previously reported. Consistent with this genetic association in humans, we show that deficiency of GPR65 in mice resulted in markedly exacerbated disease in the MC903 experimental model of atopic dermatitis. Deficiency of GPR65 also increased neutrophil migration in vitro. Moreover, GPR65 deficiency in mice resulted in higher expression of the inflammatory cytokine TNF-α by T cells. In humans, CD4+ T cells from rs8005161 heterozygous in iduals expressed higher levels of TNF-α after PMA/ionomycin stimulation, particularly under pH 6 conditions. pH sensing by GPR65 appears to be important for regulating the pathogenesis of atopic dermatitis.
Publisher: American Chemical Society (ACS)
Date: 04-11-2008
DOI: 10.1021/JA8039585
Abstract: One-pot approach to couple the crystallization of CaCO(3) nanoparticles and the in situ symmetry-breaking assembly of these crystallites into hollow spherical shells was developed under the templating effect of a soluble starch. Further functional study using HP-a as an anticancer drug carrier (DOX) demonstrated its advantages for localizing drug release by the pH value-sensitive structure and enhancing cytotoxicity by increasing cellular uptake, perinuclear accumulation, and nuclear entry.
Publisher: Wiley
Date: 2014
DOI: 10.1038/ICB.2013.86
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.JACI.2019.02.008
Abstract: The function of follicular regulatory T (T We sought to investigate the phenotype, function, and clinical relevance of T The phenotype and frequency of tonsillar and circulating T T Impairment in T
Publisher: Springer New York
Date: 2018
DOI: 10.1007/978-1-4939-7474-0_8
Abstract: Upon priming by antigens, B cells undergo activation, proliferation, and differentiation into antibody-secreting cells. During thymus-dependent (TD) antibody responses, the proliferation and differentiation of antigen-primed B cells essentially rely on the helper function from CD4
Publisher: Wiley
Date: 19-04-2010
DOI: 10.1111/J.1742-4658.2010.07628.X
Abstract: Roquin is an E3 ubiquitin ligase with a poorly understood but essential role in preventing T-cell-mediated autoimmune disease and in microRNA-mediated repression of inducible costimulator (Icos) mRNA. Roquin and its mammalian paralogue membrane-associated nucleic acid binding protein (MNAB) define a protein family distinguished by an approximately 200 amino acid domain of unknown function, ROQ, that is highly conserved from mammals to invertebrates and is flanked by a RING-1 zinc finger and a CCCH zinc finger. Here we show that human, Drosophila and Caenorhabditis elegans Roquin and human MNAB localize to the cytoplasm and upon stress are concentrated in stress granules, where stalled mRNA translation complexes are stored. The ROQ domain is necessary and sufficient for localization to arsenite-induced stress granules and to induce these structures upon overexpression, and is required to trigger Icos mRNA decay. Gel-shift, SPR and footprinting studies show that an N-terminal fragment centred on the ROQ domain binds RNA from the Icos 3'-untranslated region comprising the minimal sequence for Roquin-mediated repression, adjacent to the miR-101 sequence complementarity. These findings identify Roquin as an RNA-binding protein and establish a specific function for the ROQ protein domain in mRNA homeostasis. Structured digital abstract * MINT-7711163: TIA-1 (uniprotkb:P31483) and Roquin (uniprotkb:Q4VGL6) colocalize (MI:0403) by fluorescence microscopy (MI:0416) * MINT-7711475: RLE-1 (uniprotkb:O45962) and TIA-1 (uniprotkb:P31483) colocalize (MI:0403) by fluorescence microscopy (MI:0416) * MINT-7711487: DmRoquin (uniprotkb:Q9VV48) and TIA-1 (uniprotkb:P31483) colocalize (MI:0403) by fluorescence microscopy (MI:0416) * MINT-7711447, MINT-7711460: MNAB (uniprotkb:Q9HBD1) and TIA-1 (uniprotkb:P31483) colocalize (MI:0403) by fluorescence microscopy (MI:0416) * MINT-7711176: eIF3 (uniprotkb:P55884) and Roquin (uniprotkb:Q4VGL6) colocalize (MI:0403) by fluorescence microscopy (MI:0416) * MINT-7711192: DCP1A (uniprotkb:Q9NPI6) and TIA-1 (uniprotkb:P31483) colocalize (MI:0403) by fluorescence microscopy (MI:0416).
Publisher: American Association for the Advancement of Science (AAAS)
Date: 11-2019
DOI: 10.1126/SCIIMMUNOL.AAW0402
Abstract: ICOS- and IL-23–mediated costimulation are important for driving in vivo activation of antigen-specific MAIT cells.
Publisher: Springer Science and Business Media LLC
Date: 21-11-2020
Publisher: American Association for the Advancement of Science (AAAS)
Date: 13-10-2021
DOI: 10.1126/SCITRANSLMED.ABB6981
Abstract: Macrophage-tumor chimeric exosomes inhibit tumor growth in multiple mouse models by stimulating the immune response and tumor microenvironment.
Publisher: Springer Science and Business Media LLC
Date: 26-07-2021
DOI: 10.1038/S41551-021-00764-3
Abstract: Choroidal neovascularization induced by age-related macular degeneration and retinal neovascularization induced by diabetic retinopathy-two leading causes of blindness-are often treated using antibodies targeting vascular endothelial growth factor (VEGF). Here we report a strong association between inflammation and high VEGF expression in aqueous humour s les from patients with choroidal or retinal neovascularization, and show that intravitreally injected exosomes derived from regulatory T cells and conjugated with an anti-VEGF antibody via a peptide linker that is cleavable by matrix metalloproteinases markedly suppressed ocular neovascularization in mouse and non-human primate models of choroidal neovascularization. The engineered exosomes, which selectively accumulate in the neovascularization lesions, could be adapted for other combination therapies of therapeutic antibodies and anti-inflammatory cargo.
Publisher: Springer US
Date: 22-11-2021
DOI: 10.1007/978-1-0716-1736-6_21
Abstract: T follicular helper (Tfh) cells are a subset of specialized CD4
Publisher: American Association for the Advancement of Science (AAAS)
Date: 13-09-2019
DOI: 10.1126/SCIIMMUNOL.AAY7668
Abstract: IL-6 inhibits the expression of IL-2Rβ (CD122) in germinal center T FH cells to maintain IL-2 hyporesponsiveness (see the related Research Article by Papillion et al . ).
Publisher: Annual Reviews
Date: 20-05-2016
DOI: 10.1146/ANNUREV-IMMUNOL-041015-055605
Abstract: Although T cell help for B cells was described several decades ago, it was the identification of CXCR5 expression by B follicular helper T (Tfh) cells and the subsequent discovery of their dependence on BCL6 that led to the recognition of Tfh cells as an independent helper subset and accelerated the pace of discovery. More than 20 transcription factors, together with RNA-binding proteins and microRNAs, control the expression of chemotactic receptors and molecules important for the function and homeostasis of Tfh cells. Tfh cells prime B cells to initiate extrafollicular and germinal center antibody responses and are crucial for affinity maturation and maintenance of humoral memory. In addition to the roles that Tfh cells have in antimicrobial defense, in cancer, and as HIV reservoirs, regulation of these cells is critical to prevent autoimmunity. The realization that follicular T cells are heterogeneous, comprising helper and regulatory subsets, has raised questions regarding a possible ision of labor in germinal center B cell selection and elimination.
Publisher: American Society for Clinical Investigation
Date: 26-08-2020
DOI: 10.1172/JCI141054
Publisher: Elsevier BV
Date: 09-2020
Publisher: Springer Science and Business Media LLC
Date: 16-10-2021
Publisher: Springer Science and Business Media LLC
Date: 11-07-2022
DOI: 10.1038/S41590-022-01253-8
Abstract: The identification of CD4
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-01-2018
Abstract: The IL-33-type 2 innate lymphoid cell (ILC2) axis has an important role in tissue homeostasis, inflammation, and wound healing. However, the relative importance of this innate immune pathway for immunotherapy against inflammation and tissue damage remains unclear. Here, we show that treatment with recombinant mouse IL-33 prevented renal structural and functional injury and reduced mortality in mice subjected to ischemia-reperfusion injury (IRI). Compared with control-treated IRI mice, IL-33–treated IRI mice had increased levels of IL-4 and IL-13 in serum and kidney and more ILC2, regulatory T cells (Tregs), and anti-inflammatory (M2) macrophages. Depletion of ILC2, but not Tregs, substantially abolished the protective effect of IL-33 on renal IRI. Adoptive transfer of ex vivo –expanded ILC2 prevented renal injury in mice subjected to IRI. This protective effect associated with induction of M2 macrophages in kidney and required ILC2 production of hiregulin. Treatment of mice with IL-33 or ILC2 after IRI was also renoprotective. Furthermore, in a humanized mouse model of renal IRI, treatment with human IL-33 or transfer of ex vivo –expanded human ILC2 ameliorated renal IRI. This study has uncovered a major protective role of the IL-33–ILC2 axis in renal IRI that could be potentiated as a therapeutic strategy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2011
Publisher: Springer Science and Business Media LLC
Date: 03-08-2016
DOI: 10.1038/NI.3543
Abstract: During unresolved infections, some viruses escape immunological control and establish a persistant reservoir in certain cell types, such as human immunodeficiency virus (HIV), which persists in follicular helper T cells (TFH cells), and Epstein-Barr virus (EBV), which persists in B cells. Here we identified a specialized group of cytotoxic T cells (TC cells) that expressed the chemokine receptor CXCR5, selectively entered B cell follicles and eradicated infected TFH cells and B cells. The differentiation of these cells, which we have called 'follicular cytotoxic T cells' (TFC cells), required the transcription factors Bcl6, E2A and TCF-1 but was inhibited by the transcriptional regulators Blimp1, Id2 and Id3. Blimp1 and E2A directly regulated Cxcr5 expression and, together with Bcl6 and TCF-1, formed a transcriptional circuit that guided TFC cell development. The identification of TFC cells has far-reaching implications for the development of strategies to control infections that target B cells and TFH cells and to treat B cell-derived malignancies.
Publisher: Wiley
Date: 2021
DOI: 10.1002/CTI2.1338
Abstract: The benefit of Se supplementation in rheumatoid arthritis (RA) has been tested in clinical trials, but results remain inconclusive. The objective of this study was to specifically investigate the potential benefit of supranutritional Se by examining human s les from an area with supranutritional Se intake and testing a mouse model of RA. Peripheral blood mononuclear cells (PBMCs) from RA patients ( N = 57) and healthy controls (HC, N = 71) from an area of supranutritional Se intake (Enshi, Hubei, China) were analysed by flow cytometry. Serum cytokine and Se levels were measured by cytometric beads array (CBA) and inductively coupled plasma mass spectrometry (ICP‐MS), respectively. With sufficient or supranutritional selenium intake, mice were induced with collagen‐induced arthritis (CIA) and examined for disease activity and immunopathology. The influence of Se supplementation in the generation of RANKL‐expressing osteoclastogenic CD4 + T cells was investigated by in vitro assays. In Enshi city, HC showed the above‐normal concentrations of serum Se concentrations while RA patients were enriched in the normal range (70–150 ng mL −1 ) or below. RA patients with higher Se levels demonstrated milder disease and lower levels of C‐reactive protein, IL‐6, RANKL and Th17 cells. In the mouse CIA model, supranutritional Se supplementation delayed disease onset, ameliorated joint pathology and reduced CD4 + CD44 + RANKL + T cells. Se supplementation could suppress RANKL expression in cultured mouse Th17 cells. Supranutritional Se suppresses RANKL‐expressing osteoclastogenic CD4 + T cells and could be beneficial to RA, which warrants formal testing in randomised clinical trials.
Publisher: Wiley
Date: 2021
DOI: 10.1002/CTI2.1293
Abstract: Low‐dose interleukin‐2 (IL‐2) has shown promising clinical benefits in the treatment of systemic lupus erythematosus (SLE), but how this therapy alleviates pathogenic humoral immunity remains not well understood. The dilemma is that IL‐2 can suppress both follicular helper and regulatory T (Tfh and Tfr) cells, which counteract each other in regulating autoantibody production. Female NZB/W F1 mice received recombinant human IL‐2 (3 × 10 4 IU/dose) in three treatment regimens: (1) short, daily for 7 days (2) medium, daily for 14 days, and (3) long, every second day for 28 days. Tfh (Foxp3 − CXCR5 + Bcl6 + ), Tfr (Foxp3 + CXCR5 + Bcl6 + ), germinal centre (GC, B220 + GL‐7 + Fas + ) and antibody‐secreting cell (ASC, B220 − CD138 + TACI + ) were analysed by flow cytometry. Serum anti‐dsDNA level was determined by ELISA. Kidney pathology was evaluated by H& E and immunofluorescence staining. Circulating Tfh and Tfr cells in SLE patients treated with low‐dose IL‐2 from a previous clinical trial (NCT02084238) was analysed. Low‐dose IL‐2 treatment consistently increased Tfr/Tfh ratio in mice and SLE patients, because of a stronger suppression on Tfh cells than Tfr cells. Three treatment regimens revealed distinct immunological features. Tfh suppression was observed in all regimens, but Tfr suppression and GC reduction were recorded in just medium and long regimens. Only the long treatment regimen resulted in inhibited ASC differentiation in spleen, which was accompanied by reduced anti‐dsDNA titres and ameliorated kidney pathology. Low‐dose IL‐2 therapy increases the Tfr/Tfh ratio, and a less frequent and prolonged treatment can alleviate pathogenic humoral immunity and improve renal function.
Publisher: Elsevier BV
Date: 12-2018
Abstract: CD8
Publisher: Elsevier BV
Date: 02-2022
DOI: 10.1016/J.JACI.2021.06.023
Abstract: Local immunoglobulin hyperproduction is observed in nasal polyps (NPs) with and without ectopic lymphoid tissues (eLTs). Our aim was to identify the T-cell subsets involved in local immunoglobulin production independent of eLTs in NPs. The localization, abundance, and phenotype of CD4 Accumulation of PD-1 PD-1
Publisher: Oxford University Press (OUP)
Date: 04-02-2013
DOI: 10.1093/RHEUMATOLOGY/KES374
Abstract: To compare features of SS in RA with primary SS and RA without SS. Patients hospitalized between January 2007 and December 2010 were retrospectively studied. Seventy-four cases of overlap RA and SS (RA/SS) among 509 cases of RA were identified. Cases of SS (n = 187) detected during the same period acted as controls. Among those with RA/SS, there were 46 cases of RA-onset SS and 12 cases of SS-onset RA. Sixteen patients had simultaneous-onset RA and SS. Compared with RA without SS, RA/SS patients had more severe arthritis a higher incidence of haematological abnormality, fever and rash and a higher frequency of RF, ANAs and anti-SSA and anti-SSB antibodies (P < 0.05). Compared with primary SS, RA/SS patients were older, had more severe arthritis, anaemia and lung involvement a lower incidence of fever, rash, leucopenia, thrombocytopenia and hyperthyroidism and a higher frequency of RF, anti-keratin antibody, anti-perinuclear factor and anti-cyclic citrullinated antibodies (P < 0.05). Compared with RA and primary SS, RA/SS patients had higher disease activity scores of both RA and SS. RA/SS patients have distinctive features, with more complications and systemic involvement. In addition, disease activity is higher in RA/SS.
Publisher: Wiley
Date: 10-12-2019
Publisher: Elsevier BV
Date: 09-2009
DOI: 10.1016/J.IMMUNI.2009.07.002
Abstract: Follicular helper T (Tfh) cells provide selection signals to germinal center B cells, which is essential for long-lived antibody responses. High CXCR5 and low CCR7 expression facilitates their homing to B cell follicles and distinguishes them from T helper 1 (Th1), Th2, and Th17 cells. Here, we showed that Bcl-6 directs Tfh cell differentiation: Bcl-6-deficient T cells failed to develop into Tfh cells and could not sustain germinal center responses, whereas forced expression of Bcl-6 in CD4(+) T cells promoted expression of the hallmark Tfh cell molecules CXCR5, CXCR4, and PD-1. Bcl-6 bound to the promoters of the Th1 and Th17 cell transcriptional regulators T-bet and RORgammat and repressed IFN-gamma and IL-17 production. Bcl-6 also repressed expression of many microRNAs (miRNAs) predicted to control the Tfh cell signature, including miR-17-92, which repressed CXCR5 expression. Thus, Bcl-6 positively directs Tfh cell differentiation, through combined repression of miRNAs and transcription factors.
Publisher: Springer New York
Date: 2015
DOI: 10.1007/978-1-4939-2498-1_17
Abstract: Follicular helper T (Tfh) cells are the helper T-cell subset that localizes in germinal centers within secondary lymphoid organs. They support B cells to produce high-affinity antibodies and generate B-cell memory. By contrast, follicular regulatory T (Tfr) cells localize in germinal centers to suppress B-cell responses. Coordinately regulating antibody responses, Tfh and Tfr cells play a critical role for vaccination, infectious disease control, and the development of autoimmune diseases. Although bona fide Tfh and Tfr cells are hardly detected in human blood, circulating Tfh and Tfr memory cells in blood can be used to investigate their functions in health and disease. We have developed a comprehensive flow cytometric analysis to define different circulating Tfh and Tfr populations within CXCR5(+) CD4(+) T-cell population in human blood, based on numerous cell surface markers including CD25, CD127, CCR7, PD-1, CXCR3, and CCR6.
Publisher: Wiley
Date: 05-08-2010
DOI: 10.1002/JOR.21138
Abstract: Heparanase (HPSE) is known to be involved in fracture repair in mice, but its presence and function in human bone formation remains unclear. Our aim was to determine the expression of HPSE in human bone forming osteoblasts and to better understand its role in osteogenesis. HPSE protein expression and enzymatic activity were demonstrated in osteoblasts isolated from trabecular bone specimens of patients with osteoporosis (OP) and from healthy subjects, although the levels differed markedly. Thus, low levels of HPSE expression were observed in osteoporotic osteoblasts, including in the nucleus compared to those from healthy subjects. Notably, HPSE gene expression was associated with alkaline phosphatase (ALP) activity, the bone turnover marker. Gene profile studies demonstrated that osteogenic genes were downregulated in osteoporotic osteoblasts. We further exposed osteoblasts to exogenous HPSE and found that the level of histone H3 phosphorylation was increased. We provide evidence, for the first time, demonstrating that HPSE expresses and functions in human osteoblasts. Our data suggest that previously undescribed function of HPSE-mediated osteoblastogenesis through regulation of osteogenic gene expression and histone H3 modification. HPSE upregulation may be a novel therapeutic approach in the prevention and treatment of OP.
Publisher: eLife Sciences Publications, Ltd
Date: 19-01-2023
DOI: 10.7554/ELIFE.82217
Abstract: A defining feature of successful vaccination is the ability to induce long-lived antigen-specific memory cells. T follicular helper (Tfh) cells specialize in providing help to B cells in mounting protective humoral immunity in infection and after vaccination. Memory Tfh cells that retain the CXCR5 expression can confer protection through enhancing humoral response upon antigen re-exposure but how they are maintained is poorly understood. CXCR5 + memory Tfh cells in human blood are ided into Tfh1, Tfh2, and Tfh17 cells by the expression of chemokine receptors CXCR3 and CCR6 associated with Th1 and Th17, respectively. Here, we developed a new method to induce Tfh1, Tfh2, and Tfh17-like (iTfh1, iTfh2, and iTfh17) mouse cells in vitro. Although all three iTfh subsets efficiently support antibody responses in recipient mice with immediate immunization, iTfh17 cells are superior to iTfh1 and iTfh2 cells in supporting antibody response to a later immunization after extended resting in vivo to mimic memory maintenance. Notably, the counterpart human Tfh17 cells are selectively enriched in CCR7 + central memory Tfh cells with survival and proliferative advantages. Furthermore, the analysis of multiple human cohorts that received different vaccines for HBV, influenza virus, tetanus toxin or measles revealed that vaccine-specific Tfh17 cells outcompete Tfh1 or Tfh2 cells for the persistence in memory phase. Therefore, the complementary mouse and human results showing the advantage of Tfh17 cells in maintenance and memory function supports the notion that Tfh17-induced immunization might be preferable in vaccine development to confer long-term protection.
Publisher: Springer Science and Business Media LLC
Date: 08-08-2016
DOI: 10.1038/NM.4148
Abstract: Systemic lupus erythematosus (SLE) is a potentially life-threatening autoimmune disease characterized by altered balance of activity between effector and regulatory CD4(+) T cells. The homeostasis of CD4(+) T cell subsets is regulated by interleukin (IL)-2, and reduced production of IL-2 by T cells is observed in in iduals with SLE. Here we report that treatment with low-dose recombinant human IL-2 selectively modulated the abundance of regulatory T (Treg) cells, follicular helper T (TFH) cells and IL-17-producing helper T (TH17) cells, but not TH1 or TH2 cells, accompanied by marked reductions of disease activity in patients with SLE.
Publisher: Frontiers Media SA
Date: 13-07-2021
DOI: 10.3389/FIMMU.2021.626199
Abstract: Crosstalk between T and B cells is crucial for generating high-affinity, class-switched antibody responses. The roles of CD4 + T cells in this process have been well-characterised. In contrast, regulation of antibody responses by CD8 + T cells is significantly less defined. CD8 + T cells are principally recognised for eliciting cytotoxic responses in peripheral tissues and forming protective memory. However, recent findings have identified a novel population of effector CD8 + T cells that co-opt a differentiation program characteristic of CD4 + T follicular helper (Tfh) cells, upregulate the chemokine receptor CXCR5 and localise to B cell follicles. While it has been shown that CXCR5 + CD8 + T cells mediate the removal of viral reservoirs in the context of follicular-trophic viral infections and maintain the response to chronic insults by virtue of progenitor/stem-like properties, it is not known if CXCR5 + CD8 + T cells arise during acute peripheral challenges in the absence of follicular infection and whether they influence B cell responses in vivo in these settings. Using the ovalbumin-specific T cell receptor transgenic (OT-I) system in an adoptive transfer-immunisation/infection model, this study demonstrates that CXCR5 + CD8 + T cells arise in response to protein immunisation and peripheral viral infection, displaying a follicular-homing phenotype, expression of cell surface molecules associated with Tfh cells and limited cytotoxic potential. Furthermore, studies assessing the B cell response in the presence of OT-I or Cxcr5 -/- OT-I cells revealed that CXCR5 + CD8 + T cells shape the antibody response to protein immunisation and peripheral viral infection, promoting class switching to IgG2c in responding B cells. Overall, the results highlight a novel contribution of CD8 + T cells to antibody responses, expanding the functionality of the adaptive immune system.
Publisher: Springer Science and Business Media LLC
Date: 08-11-2007
DOI: 10.1038/NATURE06253
Abstract: Immune responses are normally targeted against microbial pathogens and not self-antigens by mechanisms that are only partly understood. Here we define a newly discovered pathway that prevents autoimmunity by limiting the levels on T lymphocytes of aco-stimulatory receptor, the inducible T-cell co-stimulator(ICOS). In sanroque mice homozygous for an M199R mutation in the ROQ domain of Roquin (also known as Rc3h1), increased Icos expression on T cells causes the accumulation of lymphocytes that is associated with a lupus-like autoimmune syndrome. Roquin normally limits Icos expression by promoting the degradation of Icos messenger RNA.A conserved segment in the unusually long ICOS 3' untranslated mRNA is essential for regulation by Roquin. This segment comprises a 47-base-pair minimal region complementary to T-cell-expressed microRNAs including miR-101, the repressive activity of which is disrupted by base-pair inversions predicted to abrogate miR-101 binding. These findings illuminate a critical post-transcriptional pathway within T cells that regulates lymphocyte accumulation and autoimmunity, and highlights the therapeutic potential of partially antagonising the ICOS pathway.
Publisher: American Thoracic Society
Date: 15-09-2022
Publisher: Springer Science and Business Media LLC
Date: 05-04-2010
DOI: 10.1038/CMI.2010.18
Publisher: Elsevier BV
Date: 04-2022
Abstract: Follicular helper T (T
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.JACI.2017.10.014
Abstract: The contribution of ectopic lymphoid tissues (eLTs) to local immunoglobulin hyperproduction in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) is unclear. We sought to explore the cellular basis, formation mechanisms, and function of eLTs in patients with CRSwNP. We graded lymphoid aggregations in sinonasal mucosa and histologically studied their structures. The expression of lymphorganogenic factors and molecules required for immunoglobulin production was measured by using real-time PCR, and their localization was analyzed by means of immunohistochemistry and immunofluorescence. The phenotype of follicular helper T cells was analyzed by performing flow cytometry. Immunoglobulin levels were quantified by using the Bio-Plex assay or ImmunoCAP system. Nasal tissue explants were challenged ex vivo with Dermatophagoides pteronyssinus group 1 (Der p 1), and the expression of Iε-Cμ and Iε-Cγ circle transcripts was detected by using seminested PCR. Increased formation of eLTs with germinal center-like structures was discovered in patients with eosinophilic (20.69%) and noneosinophilic (17.31%) CRSwNP compared with that in patients with chronic rhinosinusitis without nasal polyps (5.66%) and control subjects (3.70%). The presence of eLTs was associated with increased expression of lymphorganogenic and inflammatory chemokines and cytokines, as well as their receptors. The expression of molecules required for immunoglobulin production, generation of follicular helper T cells, and production of IgE in eosinophilic polyps and IgG and IgA in both eosinophilic and noneosinophilic polyps were predominantly upregulated in patients with eLTs. After Der p 1 challenge ex vivo, Iε-Cμ transcript was detected only in eosinophilic polyps with eLTs but not in polyps without eLTs and noneosinophilic polyps. eLTs might support local immunoglobulin production and therefore significantly contribute to the development of CRSwNP.
Publisher: Springer Science and Business Media LLC
Date: 04-10-2021
Publisher: Wiley
Date: 15-06-2017
Abstract: Failure in enhancing antigen immunogenicity has limited the development of cancer vaccine. Inspired by effective immune responses toward microorganisms, demi‐bacteria (DB) from Bacillus are engineered as carriers for cancer vaccines. The explored hydrothermal treatment enables the Bacillus to preserve optimal pathogen morphology with intrinsic mannose receptor agonist. Meanwhile, the treated Bacillus can be further endowed with ideal hollow orous structure for efficient accommodation of antigen and adjuvant, such as CpG. Therefore, this optimal engineered nanoarchitecture allows multiple immunostimulatory elements integrate in a pattern closely resembling that of bacterial pathogens. Such pathogen mimicry greatly enhances antigen uptake and cross‐presentation, resulting in stronger immune activation suitable for cancer vaccines. Indeed, DB‐based biomimetic vaccination in mice induces synergistic cellular and humoral immune responses, achieving potent therapeutic and preventive effects against cancer. Application of microorganism‐sourced materials thus presents new opportunities for potent cancer therapy.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 24-02-2023
DOI: 10.1126/SCIIMMUNOL.ADD1728
Abstract: In antibody responses, mutated germinal center B (B GC ) cells are positively selected for reentry or differentiation. As the products from GCs, memory B cells and antibody-secreting cells (ASCs) support high-affinity and long-lasting immunity. Positive selection of B GC cells is controlled by signals received through the B cell receptor (BCR) and follicular helper T (T FH ) cell–derived signals, in particular costimulation through CD40. Here, we demonstrate that the T FH cell effector cytokine interleukin-21 (IL-21) joins BCR and CD40 in supporting B GC selection and reveal that strong IL-21 signaling prioritizes ASC differentiation in vivo. B GC cells, compared with non-B GC cells, show significantly reduced IL-21 binding and attenuated signaling, which is mediated by low cellular heparan sulfate (HS) sulfation. Mechanistically, N-deacetylase and N-sulfotransferase 1 (Ndst1)–mediated N-sulfation of HS in B cells promotes IL-21 binding and signal strength. Ndst1 is down-regulated in B GC cells and up-regulated in ASC precursors, suggesting selective desensitization to IL-21 in B GC cells. Thus, specialized biochemical regulation of IL-21 bioavailability and signal strength sets a balance between the stringency and efficiency of GC selection.
Publisher: Elsevier BV
Date: 10-2010
Abstract: Follicular helper T (Tfh) cells provide help to B cells and allow formation of long-lived antibody responses. Despite an improved understanding of the molecular program that drives Tfh cell formation, their definition remains elusive: neither follicular homing ability, Bcl-6 expression nor IL-21 secretion are exclusive properties of T cells that help B cells, and not all follicular T cells are B cell helpers. Indeed some follicular T cells appear to be suppressive. Furthermore, Tfh cells evolve during an immune response and B cells that have recently bound antigen, germinal center (GC) B cells and plasmablasts interact with phenotypically distinct Tfh cells. Here we propose that distinction between non-GC Tfh and GC Tfh cells might reconcile emerging controversies on Tfh cytokine secretion and the requirement of T-B cell interactions and SAP expression for Tfh formation.
Publisher: Springer Science and Business Media LLC
Date: 19-08-2021
DOI: 10.1038/S41590-021-00996-0
Abstract: Follicular helper T (T
Publisher: The American Association of Immunologists
Date: 15-05-2011
Abstract: High expression of CXCR5 is one of the defining hallmarks of T follicular helper cells (TFH), a CD4 Th cell subset that promotes germinal center reactions and the selection and affinity maturation of B cells. CXCR5 is also expressed on 20–25% of peripheral blood human central memory CD4 T cells (TCM), although the definitive function of these cells is not fully understood. The constitutive expression of CXCR5 on TFH cells and a fraction of circulating TCM suggests that CXCR5+ TCM may represent a specialized subset of memory-type TFH cells programmed for homing to follicles and providing B cell help. To verify this assumption, we analyzed this cell population and show its specialized function in supporting humoral immune responses. Compared with their CXCR5− TCM counterparts, CXCR5+ TCM expressed high levels of the chemokine CXCL13 and efficiently induced plasma cell differentiation and Ig secretion. We found that the distinct B cell helper qualities of CXCR5+ TCM were mainly due to high ICOS expression and pronounced responsiveness to ICOS ligand costimulation together with large IL-10 secretion. Furthermore, B cell helper attributes of CXCR5+ TCM were almost exclusively acquired on cognate interaction with B cells, but not with dendritic cells. This implies that a preferential recruitment of circulating CXCR5+ TCM to CXCL13-rich B cell follicles is required for the promotion of a quick and efficient protective secondary humoral immune response. Taken together, we propose that CXCR5+ TCM represent a distinct memory cell subset specialized in supporting Ab-mediated immune responses.
Publisher: Elsevier BV
Date: 03-2021
Publisher: Springer Science and Business Media LLC
Date: 05-01-2023
Publisher: The American Association of Immunologists
Date: 06-2016
Abstract: Immune cells cycle between a resting and an activated state. Their metabolism is tightly linked to their activation status and, consequently, functions. Ag recognition induces T lymphocyte activation and proliferation and acquisition of effector functions that require and depend on cellular metabolic reprogramming. Likewise, recognition of pathogen-associated molecular patterns by monocytes and macrophages induces changes in cellular metabolism. As obligate intracellular parasites, viruses manipulate the metabolism of infected cells to meet their structural and functional requirements. For ex le, HIV-induced changes in immune cell metabolism and redox state are associated with CD4+ T cell depletion, immune activation, and inflammation. In this review, we highlight how HIV modifies immunometabolism with potential implications for cure research and pathogenesis of comorbidities observed in HIV-infected patients, including those with virologic suppression. In addition, we highlight recently described key methods that can be applied to study the metabolic dysregulation of immune cells in disease states.
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.COI.2009.09.013
Abstract: T follicular helper (Tfh) cells were originally described as a non-polarized CD4(+) T cell subset with follicular homing capacity and a potent ability to induce antibody production from B cells. However, a number of studies published in the past year have revealed a degree of heterogeneity within the germinal center CD4(+) T cell population, which suggests additional complexity. The overzealous activities of Tfh cells, or inappropriate expression of certain cytokines, represent new pathways for the development of autoimmune diseases. This review focuses on current progress in unraveling the biology of Tfh cells in health and disease, and understanding the relationship of Tfh cells to other CD4(+) T cell lineages.
Publisher: BMJ
Date: 07-12-2009
Abstract: MicroRNA (miRNA), a group of short non-coding RNA of approximately 20-22 nucleotides modulating the stability and translational efficiency of target messenger RNA, present an important new layer controlling gene expression. Hundreds to a thousand miRNA have been identified and are predicted to regulate at least one-third of protein-coding transcripts in the mammalian genome. This study reviews the recent advances reinforcing the awareness that miRNA are key players in rheumatic diseases by regulating major pathogenic molecules, such as tumour necrosis factor, central signal pathways, such as type I interferon pathway and critical immunoregulatory cells, such as regulatory T cells. In animals, blockade of miRNA maturation by the deletion of Dicer or Drasha, interference with miRNA function by the mutation of Roquin and the altered expression of in idual miRNA (miR-146a) or miRNA cluster (miR-17-92) all lead to the development of autoimmune diseases. Growing evidence also reveals the differential expression of certain immunity-regulating miRNA in rheumatoid patients. The features of miRNA-mediated regulation, the direction of future miRNA study in rheumatic diseases and the application of miRNA in diagnosis, therapy and prognosis will also be briefly discussed.
Publisher: Springer Science and Business Media LLC
Date: 24-05-2021
DOI: 10.1038/S41467-021-23220-X
Abstract: Follicular helper T (T FH ) cells control antibody responses by supporting antibody affinity maturation and memory formation. Inadequate T FH function has been found in in iduals with ineffective responses to vaccines, but the mechanism underlying T FH regulation in vaccination is not understood. Here, we report that lower serum levels of the metabolic hormone leptin associate with reduced vaccine responses to influenza or hepatitis B virus vaccines in healthy populations. Leptin promotes mouse and human T FH differentiation and IL-21 production via STAT3 and mTOR pathways. Leptin receptor deficiency impairs T FH generation and antibody responses in immunisation and infection. Similarly, leptin deficiency induced by fasting reduces influenza vaccination-mediated protection for the subsequent infection challenge, which is mostly rescued by leptin replacement. Our results identify leptin as a regulator of T FH cell differentiation and function and indicate low levels of leptin as a risk factor for vaccine failure.
Publisher: Elsevier BV
Date: 12-2008
Publisher: Springer Science and Business Media LLC
Date: 15-09-2022
DOI: 10.1038/S41467-022-33116-Z
Abstract: Anti-cancer immunity and response to immune therapy is influenced by the metabolic states of the tumours. Immune checkpoint blockade therapy (ICB) is known to involve metabolic adaptation, however, the mechanism is not fully known. Here we show, by metabolic profiling of plasma s les from melanoma-bearing mice undergoing anti-PD1 and anti-CTLA4 combination therapy, that higher levels of purine metabolites, including inosine, mark ICB sensitivity. Metabolic profiles of ICB-treated human cancers confirm the association between inosine levels and ICB sensitivity. In mouse models, inosine supplementation sensitizes tumours to ICB, even if they are intrinsically ICB resistant, by enhancing T cell-mediated cytotoxicity and hence generating an immunologically hotter microenvironment. We find that inosine directly inhibits UBA6 in tumour cells, and lower level of UBA6 makes the tumour more immunogenic and this is reflected in favourable outcome following ICB therapy in human melanomas. Transplanted mouse melanoma and breast cancer cells with genetic ablation of Uba6 show higher sensitivity to ICB than wild type tumours. Thus, we provide evidence of an inosine-regulated UBA6-dependent pathway governing tumour-intrinsic immunogenicity and hence sensitivity to immune checkpoint inhibition, which might provide targets to overcome ICB resistance.
Publisher: Springer Science and Business Media LLC
Date: 10-2009
DOI: 10.1038/NATURE08530
Publisher: Cold Spring Harbor Laboratory
Date: 30-11-2022
DOI: 10.1101/2022.11.28.22282728
Abstract: Uveitis is a common cause of blindness and classified as infectious or non-infectious types. Non-infectious uveitis is often secondary to systemic autoimmune diseases, with Behçet’s disease (BD) and Vogt-Koyanagi-Harada disease (VKHD) as the two most common causes. Uveitis in BD and VKHD often show similar clinical manifestations, but the underlying immunopathogenesis remains unclear. We collected immune cell infiltrates in aqueous humour of BD and VKHD uveitis patients and analysed them by single-cell RNA paired with T cell receptor (TCR) sequencing. T cells were found as the dominant immune cell infiltration. Intriguingly, a majority of CD4 + in T cell infiltrates was only observed in VKHD but not in BD. In agreement with this discrepancy between VKHD and BD, T cell clonality analysis and Clonotype Neighbour Graph Analysis (CoNGA) also revealed a selective expansion of pro-inflammatory CD4 + T cell clones in VKHD. In contrast, BD showed a selective expansion of pro-inflammatory CD8 + T cell clones. Our study reveals distinct immunopathogenesis of uveitis driven by CD4 + T cells in VKHD and by CD8 + T cells in BD, and therefore suggests differential approaches for their diagnosis and therapy.
Publisher: Wiley
Date: 2020
DOI: 10.1002/CTI2.1105
Publisher: Public Library of Science (PLoS)
Date: 07-10-2021
DOI: 10.1371/JOURNAL.PPAT.1009858
Abstract: Autoimmune diseases are often treated by glucocorticoids and immunosuppressive drugs that could increase the risk for infection, which in turn deteriorate disease and cause mortality. Low-dose IL-2 (Ld-IL2) therapy emerges as a new treatment for a wide range of autoimmune diseases. To examine its influence on infection, we retrospectively studied 665 patients with systemic lupus erythematosus (SLE) including about one third receiving Ld-IL2 therapy, where Ld-IL2 therapy was found beneficial in reducing the incidence of infections. In line with this clinical observation, IL-2 treatment accelerated viral clearance in mice infected with influenza A virus or lymphocytic choriomeningitis virus (LCMV). Noticeably, despite enhancing anti-viral immunity in LCMV infection, IL-2 treatment exacerbated CD8 + T cell-mediated immunopathology. In summary, Ld-IL2 therapy reduced the risk of infections in SLE patients and enhanced the control of viral infection, but caution should be taken to avoid potential CD8 + T cell-mediated immunopathology.
Publisher: Springer Science and Business Media LLC
Date: 09-07-2019
DOI: 10.1038/S41584-019-0254-2
Abstract: As a hallmark of autoimmune rheumatic diseases, autoantibodies have been used in diagnosis for decades. However, the immunological mechanism underlying their generation has only become clear following the identification of T follicular helper (T
Publisher: Elsevier BV
Date: 05-2021
Publisher: American Chemical Society (ACS)
Date: 30-12-2021
Publisher: Oxford University Press (OUP)
Date: 18-06-2023
Abstract: Vaccination stands as the cornerstone in the battle against infectious diseases, and its efficacy hinges on several host-related factors like genetics, age, and metabolic status. Vulnerable populations, such as malnourished in iduals, the obese, and the elderly, commonly exhibit diminished vaccine responses and efficacy. While the specific factors contributing to this impairment may vary, these in iduals typically display a degree of metabolic dysregulation, thereby underscoring its potential significance as a fundamental determinant of suboptimal vaccine responses. The emerging field of immunometabolism aims to unravel the intricate interplay between immune regulation and metabolic pathways, and recent research has revealed erse metabolic signatures linked to various vaccine responses and outcomes. In this review, we summarize the major metabolic pathways utilized by B and T cells during vaccine responses, their complex and varied metabolic requirements, and the impact of micronutrients and metabolic hormones on vaccine outcomes. Furthermore, we examine how systemic metabolism influences vaccine responses and the evidence suggesting that metabolic dysregulation in vulnerable populations can lead to impaired vaccine responses. Lastly, we reflect on the challenge of proving causality with respect to the contribution of metabolic dysregulation to poor vaccine outcomes, and highlight the need for a systems biology approach that combines multimodal profiling and mathematical modelling to reveal the underlying mechanisms of such complex interactions.
Publisher: Wiley
Date: 2023
DOI: 10.1002/CTI2.1461
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.CELREP.2015.12.006
Abstract: Naturally acquired immunity to malaria develops only after years of repeated exposure to Plasmodium parasites. Despite the key role antibodies play in protection, the cellular processes underlying the slow acquisition of immunity remain unknown. Using mouse models, we show that severe malaria infection inhibits the establishment of germinal centers (GCs) in the spleen. We demonstrate that infection induces high frequencies of T follicular helper (Tfh) cell precursors but results in impaired Tfh cell differentiation. Despite high expression of Bcl-6 and IL-21, precursor Tfh cells induced during infection displayed low levels of PD-1 and CXCR5 and co-expressed Th1-associated molecules such as T-bet and CXCR3. Blockade of the inflammatory cytokines TNF and IFN-γ or T-bet deletion restored Tfh cell differentiation and GC responses to infection. Thus, this study demonstrates that the same pro-inflammatory mediators that drive severe malaria pathology have detrimental effects on the induction of protective B cell responses.
Publisher: Wiley
Date: 04-11-2020
DOI: 10.1111/ALL.14639
Start Date: 2011
End Date: 12-2014
Amount: $315,000.00
Funder: Australian Research Council
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