73 results found
Copland A, Mackie GM, Scarfe L, et al., 2023, <i>Salmonella</i>cancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity
<jats:title>Summary</jats:title><jats:p>Bacterial cancer therapy (BCT) is a promising therapeutic for solid tumours.<jats:italic>Salmonella enterica</jats:italic>Typhimurium (STm) is well-studied amongst bacterial vectors due to advantages in genetic modification and metabolic adaptation. A longstanding paradox is the redundancy of T cells for treatment efficacy; instead, STm BCT depends on innate phagocytes for tumour control. Here, we used distal T cell receptor (TCR) reporter mice (<jats:italic>Nr4a3-Tocky-Ifng-YFP</jats:italic>) and a colorectal cancer (CRC) model to interrogate T cell activity during BCT with attenuated STm. We found that colonic TILs exhibited a variety of activation defects, including IFN-γ production decoupled from TCR signalling, decreased polyfunctionality and reduced T<jats:sub>CM</jats:sub>formation. Modelling of T-cell–tumour interactions with a tumour organoid platform revealed an intact TCR signalosome, but paralysed metabolic reprogramming due to inhibition of the master metabolic controller, c-Myc. Restoration of c-Myc by deletion of the bacterial asparaginase<jats:italic>ansB</jats:italic>reinvigorated T cell activation, but at the cost of decreased metabolic control of the tumour by STm. This work shows for the first time that T cells are metabolically defective during BCT, but also that this same phenomenon is inexorably tied to intrinsic tumour suppression by the bacterial vector.</jats:p>
Tan BJY, Sugata K, Ono M, et al., 2022, HTLV-1 persistence and leukemogenesis: A game of hide-and-seek with the host immune system, FRONTIERS IN IMMUNOLOGY, Vol: 13, ISSN: 1664-3224
Whyte CEE, Singh K, Burton OTT, et al., 2022, Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits (vol 219, e2021239107142022cpg , 2022), JOURNAL OF EXPERIMENTAL MEDICINE, Vol: 219, ISSN: 0022-1007
Almeida-Santos J, Berkachy R, Tye CA, et al., 2022, Temporal profiling of CD4 T-cell activation and differentiation upon SARS-CoV-2 spike protein immunisation
<jats:title>ABSTRACT</jats:title><jats:p>CD4 T-cells require T-cell receptor (TCR) signalling for their activation and differentiation. Foxp3+ regulatory T-cells (Treg) are dependent on TCR signals for their differentiation and suppressive function. However, it is not fully known how TCR signalling controls the differentiation of polyclonal CD4 T-cells upon antigen recognition at the single-cell level in vivo. In this study, using Nr4a3-Tocky (<jats:underline>T</jats:underline>imer-<jats:underline>o</jats:underline>f-<jats:underline>c</jats:underline>ell-<jats:underline>k</jats:underline>inetics-and-activit<jats:underline>y</jats:underline>), which analyses temporal changes of antigen-reactive T-cells following TCR signalling, we investigated T-cell response to Spike protein fragments (S1a, S1b, S2a, and S2b) upon immunisation. We show that S1a and S2a induced the differentiation of PD1<jats:sup>hi</jats:sup>CXCR5<jats:sup>+</jats:sup> T follicular helper (Tfh) cells, which is related to CD4 T-cell immunogenicity. In contrast, S1b induced CD25<jats:sup>hi</jats:sup>GITR<jats:sup>hi</jats:sup>PD-1<jats:sup>int</jats:sup> Treg, which intermittently received TCR signalling. Using Foxp3-Tocky, which analyses <jats:italic>Foxp3</jats:italic> transcriptional dynamics, the S1b-reactive Treg sustained <jats:italic>Foxp3</jats:italic> transcription over time, which is a hallmark of activated Treg. Foxp3 fate-mapping showed that the S1b-reactive Treg were derived not from pre-existing thymic Treg, suggesting Foxp3 induction in non-Treg cells. Thus, the current study reveals temporally dynamic differentiation of CD4 T-cells and Treg upon immunisation in the polyclonal TCR repertoire.</jats:p>
Whyte CE, Singh K, Burton OT, et al., 2022, Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits, JOURNAL OF EXPERIMENTAL MEDICINE, Vol: 219, ISSN: 0022-1007
Hamilton A, Rizzo R, Brod S, et al., 2022, The immunomodulatory effects of social isolation in mice are linked to temperature control, BRAIN BEHAVIOR AND IMMUNITY, Vol: 102, Pages: 179-194, ISSN: 0889-1591
Bozhanova G, Hassan J, Appleton L, et al., 2022, CD4 T cell dynamics shape the immune response to combination oncolytic herpes virus and BRAF inhibitor therapy for melanoma, JOURNAL FOR IMMUNOTHERAPY OF CANCER, Vol: 10
Tan BJY, Sugata K, Reda O, et al., 2021, HTLV-1 infection promotes excessive T cell activation and transformation into adult T cell leukemia/lymphoma, JOURNAL OF CLINICAL INVESTIGATION, Vol: 131, ISSN: 0021-9738
Bortoluzzi S, Dashtsoodol N, Engleitner T, et al., 2021, Brief homogeneous TCR signals instruct common iNKT progenitors whose effector diversification is characterized by subsequent cytokine signaling, IMMUNITY, Vol: 54, Pages: 2497-+, ISSN: 1074-7613
Appleton E, Hassan J, Hak CCW, et al., 2021, Kickstarting Immunity in Cold Tumours: Localised Tumour Therapy Combinations With Immune Checkpoint Blockade, FRONTIERS IN IMMUNOLOGY, Vol: 12, ISSN: 1664-3224
Abe H, Tanada Y, Omiya S, et al., 2021, NF-κB activation in cardiac fibroblasts results in the recruitment of inflammatory Ly6C<SUP>hi</SUP> monocytes in pressure-overloaded hearts, SCIENCE SIGNALING, Vol: 14, ISSN: 1945-0877
Ono M, 2021, Restoring control over autoimmunity by inducing Foxp3, NATURE IMMUNOLOGY, Vol: 22, Pages: 1080-1082, ISSN: 1529-2908
Lau C-I, Rowell J, Yanez DC, et al., 2021, The pioneer transcription factors Foxa1 and Foxa2 regulate alternative RNA splicing during thymocyte positive selection., Development, Vol: 148
During positive selection at the transition from CD4+CD8+ double-positive (DP) to single-positive (SP) thymocyte, TCR signalling results in appropriate MHC restriction and signals for survival and progression. We show that the pioneer transcription factors Foxa1 and Foxa2 are required to regulate RNA splicing during positive selection of mouse T cells and that Foxa1 and Foxa2 have overlapping/compensatory roles. Conditional deletion of both Foxa1 and Foxa2 from DP thymocytes reduced positive selection and development of CD4SP, CD8SP and peripheral naïve CD4+ T cells. Foxa1 and Foxa2 regulated the expression of many genes encoding splicing factors and regulators, including Mbnl1, H1f0, Sf3b1, Hnrnpa1, Rnpc3, Prpf4b, Prpf40b and Snrpd3. Within the positively selecting CD69+DP cells, alternative RNA splicing was dysregulated in the double Foxa1/Foxa2 conditional knockout, leading to >850 differentially used exons. Many genes important for this stage of T-cell development (Ikzf1-3, Ptprc, Stat5a, Stat5b, Cd28, Tcf7) and splicing factors (Hnrnpab, Hnrnpa2b1, Hnrnpu, Hnrnpul1, Prpf8) showed multiple differentially used exons. Thus, Foxa1 and Foxa2 are required during positive selection to regulate alternative splicing of genes essential for T-cell development, and, by also regulating splicing of splicing factors, they exert widespread control of alternative splicing.
Lau C-I, Rowell J, Yanez DC, et al., 2021, The pioneer transcription factors Foxa1 and Foxa2 regulate alternative RNA splicing during thymocyte positive selection, DEVELOPMENT, Vol: 148, ISSN: 0950-1991
Jennings EK, Lecky DAJ, Ono M, et al., 2021, Application of dual Nr4a1-GFP Nr4a3-Tocky reporter mice to study T cell receptor signaling by flow cytometry, STAR PROTOCOLS, Vol: 2, ISSN: 2666-1667
Jennings E, Elliot TAE, Thawait N, et al., 2020, Nr4a1 and Nr4a3 reporter mice are differentially sensitive to T cell receptor signal strength and duration., Cell Research, Vol: 33, Pages: 1-15, ISSN: 1001-0602
Nr4a receptors are activated by T cell receptor (TCR) signaling and play key roles in T cell differentiation. Which TCR signaling pathways regulate Nr4a receptors and their sensitivities to TCR signal strength and duration remains unclear. Using Nr4a1/Nur77-GFP and Nr4a3-Timer of cell kinetics and activity (Tocky) mice, we elucidate the signaling pathways governing Nr4a receptor expression. We reveal that Nr4a1-Nr4a3 are Src family kinase dependent. Moreover, Nr4a2 and Nr4a3 are attenuated by calcineurin inhibitors and bind nuclear factor of activated T cells 1 (NFAT1), highlighting a necessary and sufficient role for NFAT1 in the control of Nr4a2 and Nr4a3, but redundancy for Nr4a1. Nr4a1-GFP is activated by tonic and cognate signals during T cell development, whereas Nr4a3-Tocky requires cognate peptide:major histocompatibility complex (MHC) interactions for expression. Compared to Nr4a3-Tocky, Nr4a1-GFP is approximately 2- to 3-fold more sensitive to TCR signaling and is detectable by shorter periods of TCR signaling. These findings suggest that TCR signal duration may be an underappreciated aspect influencing the developmental fate of T cells in vivo.
T-cells play key roles in immunity to COVID-19 as well as the development of severe disease. T-cell immunity to COVID-19 is mediated through differentiated CD4+ T-cells and cytotoxic CD8+ T-cells, although their differentiation is often atypical and ambiguous in COVID-19 and single cell dynamics of key genes need to be characterized. Notably, T-cells are dysregulated in severe COVID-19 patients, although their molecular features are still yet to be fully revealed. Importantly, it is not clear which T-cell activities are beneficial and protective and which ones can contribute to the development of severe COVID-19. In this article, we examine the latest evidence and discuss the key features of T-cell responses in COVID-19, showing how T-cells are dysregulated in severe COVID-19 patients. Particularly, we highlight the impairment of FOXP3 induction in CD4+ T-cells and how the impaired FOXP3 expression can lead to the differentiation of abnormally activated (hyperactivated) T-cells and the dysregulated T-cell responses in severe patients. Furthermore, we characterise the feature of hyperactivated T-cells, showing their potential contribution to T-cell dysregulation and immune-mediated tissue destruction (immunopathology) in COVID-19.
Kalfaoglu B, Almeida-Santos J, Tye C, et al., 2020, T-cell hyperactivation and paralysis in severe COVID-19 infection revealed bysingle-cell analysis, Frontiers in Immunology, Vol: 11, ISSN: 1664-3224
Severe COVID-19 patients show various immunological abnormalities including T-cell reduction and cytokine release syndrome, which can be fatal and is a major concern of the pandemic. However, it is poorly understood how T-cell dysregulation can contribute to the pathogenesis of severe COVID-19. Here we show single cell-level mechanisms for T-cell dysregulation in severe COVID-19, demonstratingnewpathogenetic mechanisms ofT-cell activation and differentiation underlying severe COVID-19. By in silico sorting CD4+ T-cells from a single cell RNA-seq dataset, we found that CD4+ T-cells were highly activated and showed unique differentiation pathways in the lung of severe COVID-19 patients. Notably, those T-cells in severe COVID-19 patients highly expressed immunoregulatory receptors and CD25, whilst repressing the expression of FOXP3. Furthermore, we show that CD25+ hyperactivated T-cells differentiate into multiple helper T-cell lineages, showing multifaceted effector T-cells with Th1 and Th2 characteristics. Lastly, we show that CD25-expressing hyperactivated T-cells produce the protease Furin, which facilitates the viral entry of SARS-CoV-2. Collectively, CD4+T-cells from severe COVID-19 patients are hyperactivated and FOXP3-mediated negative feedback mechanisms are impaired in the lung, which may promote immunopathology. Therefore, our study proposes a new model of T-cell hyperactivation and paralysis that drives immunopathology in severe COVID-19.
Bozhanova G, Jennings V, Pedersen M, et al., 2020, Mutant BRAF small molecule inhibition enhances oncolytic herpes virus immunotherapy through increased immune cell recruitment and activation in melanoma, AACR Annual Meeting, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Piras G, Rattazzi L, Paschalidis N, et al., 2020, Immuno-<i>mood</i>ulin: A new anxiogenic factor produced by Annexin-A1 transgenic autoimmune-prone T cells, BRAIN BEHAVIOR AND IMMUNITY, Vol: 87, Pages: 689-702, ISSN: 0889-1591
Kalfaoglu B, Almeida-Santos J, Adele Tye C, et al., 2020, T-cell hyperactivation and paralysis in severe COVID-19 infection revealed by single-cell analysis
<jats:title>Abstract</jats:title><jats:p>Severe COVID-19 patients can show respiratory failure, T-cell reduction, and cytokine release syndrome (CRS), which can be fatal in both young and aged patients and is a major concern of the pandemic. However, the pathogenetic mechanisms of CRS in COVID-19 are poorly understood. Here we show single cell-level mechanisms for T-cell dysregulation in severe SARS-CoV-2 infection, and thereby demonstrate the mechanisms underlying T-cell hyperactivation and paralysis in severe COVID-19 patients. By <jats:italic>in silico</jats:italic> sorting CD4+ T-cells from a single cell RNA-seq dataset, we found that CD4+ T-cells were highly activated and showed unique differentiation pathways in the lung of severe COVID-19 patients. Notably, those T-cells in severe COVID-19 patients highly expressed immunoregulatory receptors and CD25, whilst repressing the expression of the transcription factor FOXP3 and interestingly, both the differentiation of regulatory T-cells (Tregs) and Th17 was inhibited. Meanwhile, highly activated CD4<jats:sup>+</jats:sup> T-cells express PD-1 alongside macrophages that express PD-1 ligands in severe patients, suggesting that PD-1-mediated immunoregulation was partially operating. Furthermore, we show that CD25<jats:sup>+</jats:sup> hyperactivated T-cells differentiate into multiple helper T-cell lineages, showing multifaceted effector T-cells with Th1 and Th2 characteristics. Lastly, we show that CD4<jats:sup>+</jats:sup> T-cells, particularly CD25-expressing hyperactivated T-cells, produce the protease Furin, which facilitates the viral entry of SARS-CoV-2. Collectively, CD4<jats:sup>+</jats:sup> T-cells from severe COVID-19 patients are hyperactivated and FOXP3-mediated negative feedback mechanisms are impaired in the lung, while activated CD4<jats:sup>+</jats:sup> T-cells continue to promote further viral infection through
Ono M, 2020, Control of regulatory T-cell differentiation and function by T-cell receptor signalling and Foxp3 transcription factor complexes, Immunology, Vol: 160, Pages: 24-37, ISSN: 0019-2805
The transcription factor Foxp3 controls the differentiation and function of regulatory T-cells (Treg). Studies in the past decades identified numerous Foxp3-interacting protein partners. However, it is still not clear how Foxp3 produces the Treg-type transcriptomic landscape through cooperating with its partners. Here I show the current understanding of how Foxp3 transcription factor complexes regulate the differentiation, maintenance, and functional maturation of Treg. Importantly, T-cell receptor (TCR) signalling plays central roles in Treg differentiation and Foxp3-mediated gene regulation. Thus, differentiating Treg will have recognised their cognate antigens and received TCR signals before initiating Foxp3 transcription, which is triggered by TCR induced transcription factors including NFAT, AP-1, and NF-κB. Once expressed, Foxp3 seizes TCR signal-induced transcriptional and epigenetic mechanisms through interacting with is AML1/Runx1 and NFAT. Thus Foxp3 modifies gene expression dynamics of TCR-induced genes, which constitute cardinal mechanisms for Treg-mediated immune suppression. Next, I discuss the following key topics, proposing new mechanistic models for Foxp3-mediated gene regulation: (1) how Foxp3 transcription is induced and maintained by the Foxp3-inducing enhanceosome and the Foxp3 autoregulatory transcription factor complex; (2) molecular mechanisms for effector Treg differentiation (i.e. Treg maturation); (3) how Foxp3 activates or represses its target genes through recruiting coactivators and corepressors; (4) the 'decision-making' Foxp3-containing transcription factor complex for Th17 and Treg differentiation; and (5) the roles of post-translational modification in Foxp3 regulation. Thus, this article provides cutting-edge understanding of molecular biology of Foxp3 and Treg, integrating findings by biochemical and genomic studies.
Jennings E, Elliot TAE, Thawait N, et al., 2019, Differential Nr4a1 and Nr4a3 expression discriminates tonic from activated TCR signalling events in vivo
<jats:title>Summary</jats:title><jats:p><jats:italic>Nr4a</jats:italic>receptors are activated by T cell receptor (TCR) and B cell receptor (BCR) signalling and play key roles in T cell differentiation and promoting T cell exhaustion. How TCR signalling pathways regulate Nr4a receptors and their sensitivities to different physiological types of TCR signalling (e.g. tonic versus activating) remains unknown. Here we utilise Nr4a1/Nur77-GFP and<jats:italic>Nr4a3</jats:italic>-Tocky mice to elucidate the signalling pathways that govern Nr4a receptor expression in CD4<jats:sup>+</jats:sup>and CD8<jats:sup>+</jats:sup>T cells. Our findings reveal that<jats:italic>Nr4a1-3</jats:italic>are Src family kinase-dependent. Moreover,<jats:italic>Nr4a2</jats:italic>and<jats:italic>Nr4a3</jats:italic>are abolished by calcineurin inhibitors and bind NFAT1, highlighting a necessary and sufficient role for NFAT in the control of<jats:italic>Nr4a2</jats:italic>and<jats:italic>Nr4a3</jats:italic>, but redundancy for NFAT for<jats:italic>Nr4a1</jats:italic>. During T cell development, Nr4a1 is activated by tonic signalling during TCR-beta selection in the thymus, whilst Nr4a3 requires cognate peptide:MHC interactions for expression. Thus, due to differential sensitivity of Nr4a1 and Nr4a3 to TCR signalling pathways, T cells undergoing tonic versus activating TCR signalling events can be distinguished in vivo.</jats:p>
Papaioannou E, Yanez DC, Ross S, et al., 2019, Sonic Hedgehog signaling limits atopic dermatitis via Gli2-driven immune regulation, JOURNAL OF CLINICAL INVESTIGATION, Vol: 129, Pages: 3153-3170, ISSN: 0021-9738
Mengrelis K, Lau C-I, Rowell J, et al., 2019, Sonic Hedgehog Is a Determinant of γδ T-Cell Differentiation in the Thymus, FRONTIERS IN IMMUNOLOGY, Vol: 10, ISSN: 1664-3224
Bending D, Ono M, 2019, From stability to dynamics: understanding molecular mechanisms of regulatory T cells through Foxp3 transcriptional dynamics, Clinical and Experimental Immunology, Vol: 197, Pages: 14-23, ISSN: 1365-2249
Studies on regulatory T cells (Treg) have focused on thymic Treg as a stable lineage of immunosuppressive T cells, the differentiation of which is controlled by the transcription factor forkhead box protein 3 (Foxp3). This lineage perspective, however, may constrain hypotheses regarding the role of Foxp3 and Treg in vivo, particularly in clinical settings and immunotherapy development. In this review, we synthesize a new perspective on the role of Foxp3 as a dynamically expressed gene, and thereby revisit the molecular mechanisms for the transcriptional regulation of Foxp3. In particular, we introduce a recent advancement in the study of Foxp3‐mediated T cell regulation through the development of the Timer of cell kinetics and activity (Tocky) system, and show that the investigation of Foxp3 transcriptional dynamics can reveal temporal changes in the differentiation and function of Treg in vivo. We highlight the role of Foxp3 as a gene downstream of T cell receptor (TCR) signalling and show that temporally persistent TCR signals initiate Foxp3 transcription in self‐reactive thymocytes. In addition, we feature the autoregulatory transcriptional circuit for the Foxp3 gene as a mechanism for consolidating Treg differentiation and activating their suppressive functions. Furthermore, we explore the potential mechanisms behind the dynamic regulation of epigenetic modifications and chromatin architecture for Foxp3 transcription. Lastly, we discuss the clinical relevance of temporal changes in the differentiation and activation of Treg.
Yanez DC, Sahni H, Ross S, et al., 2019, IFITM proteins drive type 2 T helper cell differentiation and exacerbate allergic airway inflammation, EUROPEAN JOURNAL OF IMMUNOLOGY, Vol: 49, Pages: 66-78, ISSN: 0014-2980
Bending D, Paduraru A, Ducker C, et al., 2018, A temporally dynamic Foxp3 autoregulatory transcriptional circuit controls the effector Treg programme, The EMBO Journal, Vol: 37, ISSN: 0261-4189
Regulatory T cells (Treg) are negative regulators of the immune response; however, it is poorly understood whether and how Foxp3 transcription is induced and regulated in the periphery during T‐cell responses. Using Foxp3‐Timer of cell kinetics and activity (Tocky) mice, which report real‐time Foxp3 expression, we show that the flux of new Foxp3 expressors and the rate of Foxp3 transcription are increased during inflammation. These persistent dynamics of Foxp3 transcription determine the effector Treg programme and are dependent on a Foxp3 autoregulatory transcriptional circuit. Persistent Foxp3 transcriptional activity controls the expression of coinhibitory molecules, including CTLA‐4 and effector Treg signature genes. Using RNA‐seq, we identify two groups of surface proteins based on their relationship to the temporal dynamics of Foxp3 transcription, and we show proof of principle for the manipulation of Foxp3 dynamics by immunotherapy: new Foxp3 flux is promoted by anti‐TNFRII antibody, and high‐frequency Foxp3 expressors are targeted by anti‐OX40 antibody. Collectively, our study dissects time‐dependent mechanisms behind Foxp3‐driven T‐cell regulation and establishes the Foxp3‐Tocky system as a tool to investigate the mechanisms behind T‐cell immunotherapies.
Bending D, Paduraru A, Ducker CB, et al., 2018, A temporally dynamic <i>Foxp3</i> autoregulatory transcriptional circuit controls the effector Treg programme, The EMBO Journal, Vol: 37, ISSN: 0261-4189
Bradley A, Hashimoto T, Ono M, 2018, Elucidating T cell activation-dependent mechanisms for bifurcation of regulatory and effector T cell differentiation by multidimensional and single cell analysis, Frontiers in Immunology, Vol: 9, ISSN: 1664-3224
In T cells, T cell receptor (TCR) signaling initiates downstream transcriptional mechanisms for T cell activation and differentiation. Foxp3-expressing regulatory T cells (Treg) require TCR signals for their suppressive function and maintenance in the periphery. It is, however, unclear how TCR signaling controls the transcriptional program of Treg. Since most of studies identified the transcriptional features of Treg in comparison to naïve T cells, the relationship between Treg and non-naïve T cells including memory-phenotype T cells (Tmem) and effector T cells (Teff) is not well understood. Here, we dissect the transcriptomes of various T cell subsets from independent datasets using the multidimensional analysis method canonical correspondence analysis (CCA). We show that at the cell population level, resting Treg share gene modules for activation with Tmem and Teff. Importantly, Tmem activate the distinct transcriptional modules for T cell activation, which are uniquely repressed in Treg. The activation signature of Treg is dependent on TCR signals and is more actively operating in activated Treg. Furthermore, by using a new CCA-based method, single-cell combinatorial CCA, we analyzed unannotated single-cell RNA-seq data from tumor-infiltrating T cells, and revealed that FOXP3 expression occurs predominantly in activated T cells. Moreover, we identified FOXP3-driven and T follicular helper-like differentiation pathways in tumor microenvironments, and their bifurcation point, which is enriched with recently activated T cells. Collectively, our study reveals the activation mechanisms downstream of TCR signals for the bifurcation of Treg and Teff differentiation and their maturation processes.
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