Publications
75 results found
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.
Bradley A, Hashimoto T, Ono M, 2018, Elucidating the activation mechanisms for bifurcation of regulatory and effector T cell fates by multidimensional single cell analysis
<jats:title>Abstract</jats:title><jats:p>In T cells, T cell receptor (TCR) signalling 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 signalling controls the transcriptional programme 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 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 analysing single cell RNA-seq data from tumour-infiltrating T cells, we revealed that FOXP3 expression occurs predominantly in activated T cells. Moreover, we identified FOXP3-driven and T follicular helper (Tfh)-like differentiation pathways in tumour 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.</jats:p>
Bending D, Martín PP, Paduraru A, et al., 2017, A Timer for analyzing temporally dynamic changes in transcription during differentiation in vivo
<jats:title>Abstract</jats:title><jats:p>Understanding the mechanisms of cellular differentiation is challenging because differentiation is initiated by signaling pathways that drive temporally dynamic processes, which are difficult to analyse in vivo. We establish a new Tool, Timer-of-cell-kinetics-and-activity (Tocky [toki], time in Japanese). Tocky uses the Fluorescent Timer protein, which spontaneously shifts its emission spectrum from blue-to-red, in combination with computer algorithms to reveal the dynamics of differentiation in vivo. Using a transcriptional target of T cell receptor (TCR)-signaling, we establish Nr4a3-Tocky to follow downstream effects of TCR signaling. Nr4a3-Tocky reveals the temporal sequence of events during regulatory T cell (Treg) differentiation and shows that persistent TCR signals occur during Treg generation. Remarkably, antigen-specific T cells at the site of autoimmune inflammation also show persistent TCR signaling. In addition, by generating Foxp3-Tocky, we reveal the in vivo dynamics of demethylation of the <jats:italic>Foxp3</jats:italic> gene. Thus, Tocky is a Tool for cell biologists to address previously inaccessible questions by directly revealing dynamic processes in vivo.</jats:p><jats:sec><jats:title>Summary</jats:title><jats:p>The authors establish a new Tool, Timer-of-cell-kinetics-and-activity (Tocky) revealing the temporal dynamics of cellular activation and differentiation in vivo. The tool analyses the temporal sequence of molecular processes during cellular differentiation and identifies cells that receive persistent signals in vivo.</jats:p></jats:sec>
Bending D, Ono M, 2017, FoxP3 partners up, NATURE IMMUNOLOGY, Vol: 18, Pages: 1181-1183, ISSN: 1529-2908
Brod S, Gobbetti T, Gittens B, et al., 2017, The impact of environmental enrichment on the murine inflammatory immune response, JCI INSIGHT, Vol: 2, ISSN: 2379-3708
Ono M, Bending D, Martin PP, 2017, Revealing the mechanism of regulatory T-cell generation in vivo by novel Fluorescent Timer reporter, Annual Meeting of the American-Association-of-Immunologists (AAI), Publisher: AMER ASSOC IMMUNOLOGISTS, ISSN: 0022-1767
Bending D, Ono M, 2017, Interplay between the skin barrier and immune cells in patients with atopic dermatitis unraveled by means of mathematical modeling, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 139, Pages: 1790-1792, ISSN: 0091-6749
Rattazzi L, Piras G, Brod S, et al., 2016, Impact of Enriched Environment on Murine T Cell Differentiation and Gene Expression Profile, FRONTIERS IN IMMUNOLOGY, Vol: 7, ISSN: 1664-3224
Heuts F, Wardzinski L, Wang CJ, et al., 2016, Cross-talk between pancreas resident innate lymphoid cells and T cells in autoimmune diabetes, International Congress of Immunology (ICI), Publisher: WILEY-BLACKWELL, Pages: 1069-1069, ISSN: 0014-2980
Bending D, Martin PP, Day H, et al., 2016, Foxp3 activation within effector T-cells controls the antigen-specific T-cell response in the contact hypersensitivity model, Annual Meeting of the European-Society-for-Dermatological-Research (ESDR), Publisher: ELSEVIER SCIENCE INC, Pages: S204-S204, ISSN: 0022-202X
Saldana JI, Solanki A, Lau C-I, et al., 2016, Sonic Hedgehog regulates thymic epithelial cell differentiation, JOURNAL OF AUTOIMMUNITY, Vol: 68, Pages: 86-97, ISSN: 0896-8411
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- Citations: 26
Fujii H, Josse J, Tanioka M, et al., 2016, Regulatory T Cells in Melanoma Revisited by a Computational Clustering of FOXP3<SUP>+</SUP> T Cell Subpopulations, JOURNAL OF IMMUNOLOGY, Vol: 196, Pages: 2885-2892, ISSN: 0022-1767
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- Citations: 15
van Logtestijn M, Caspers PJ, Kezic S, et al., 2015, Water resistance profile as a marker of skin barrier damage in atopic dermatitis patients, Journal of Dermatological Science, Vol: 81, Pages: 126-128, ISSN: 1873-569X
Sahni H, Ross S, Barbarulo A, et al., 2015, A genome wide transcriptional model of the complex response to pre-TCR signalling during thymocyte differentiation, ONCOTARGET, Vol: 6, Pages: 28646-28660
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- Citations: 15
Ono M, Tanaka RJ, 2015, Controversies concerning thymus-derived regulatory T cells: fundamental issues and a new perspective, Immunology and Cell Biology, Vol: 94, Pages: 3-10, ISSN: 1440-1711
Thymus-derived regulatory T cells (Tregs) are considered to be a distinct T-cell lineage that is genetically programmed and specialised for immunosuppression. This perspective is based on the key evidence that CD25+ Tregs emigrate to neonatal spleen a few days later than other T cells and that thymectomy of 3-day-old mice depletes Tregs only, causing autoimmune diseases. Although widely believed, the evidence has never been reproduced as originally reported, and some studies indicate that Tregs exist in neonates. Thus we examine the consequences of the controversial evidence, revisit the fundamental issues of Tregs and thereby reveal the overlooked relationship of T-cell activation and Foxp3-mediated control of the T-cell system. Here we provide a new model of Tregs and Foxp3, a feedback control perspective, which views Tregs as a component of the system that controls T-cell activation, rather than as a distinct genetically programmed lineage. This perspective provides new insights into the roles of self-reactivity, T cell–antigen-presenting cell interaction and T-cell activation in Foxp3-mediated immune regulation.
Sinclair C, Ono M, Seddon B, 2015, A Zap70-dependent feedback circuit is essential for efficient selection of CD4 lineage thymocytes, IMMUNOLOGY AND CELL BIOLOGY, Vol: 93, Pages: 406-416, ISSN: 0818-9641
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- Citations: 4
Kenefeck R, Wang CJ, Kapadi T, et al., 2015, Follicular helper T cell signature in type 1 diabetes, JOURNAL OF CLINICAL INVESTIGATION, Vol: 125, Pages: 292-303, ISSN: 0021-9738
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- Citations: 121
Ono M, Tanaka RJ, Kano M, 2014, Visualisation of the T cell differentiation programme by Canonical Correspondence Analysis of transcriptomes, BMC Genomics, Vol: 15, ISSN: 1471-2164
Fujii H, Arakawa A, Utsumi D, et al., 2014, CD81tumor-infiltrating lymphocytes at primary sites as a possible prognostic factor of cutaneous angiosarcoma, INTERNATIONAL JOURNAL OF CANCER, Vol: 134, Pages: 2393-2402, ISSN: 0020-7136
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- Citations: 72
Youssef G, Ono M, Brown SJ, et al., 2014, Identifying a Hyperkeratosis Signature in Autosomal Recessive Congenital Ichthyosis: Mdm2 Inhibition Prevents Hyperkeratosis in a Rat ARCI Model, JOURNAL OF INVESTIGATIVE DERMATOLOGY, Vol: 134, Pages: 858-861, ISSN: 0022-202X
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- Citations: 9
Youssef G, Gerner L, Naeem AS, et al., 2013, Rab3Gap1 mediates exocytosis of Claudin-1 and tight junction formation during epidermal barrier acquisition, DEVELOPMENTAL BIOLOGY, Vol: 380, Pages: 274-285, ISSN: 0012-1606
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- Citations: 10
Rattazzi L, Piras G, Ono M, et al., 2013, CD4<SUP>+</SUP> but not CD8<SUP>+</SUP> T cells revert the impaired emotional behavior of immunocompromised <i>RAG</i>-<i>1</i>-<i>deficient</i> mice, TRANSLATIONAL PSYCHIATRY, Vol: 3, ISSN: 2158-3188
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- Citations: 64
Tanaka RJ, Ono M, 2013, Skin Disease Modeling from a Mathematical Perspective, JOURNAL OF INVESTIGATIVE DERMATOLOGY, Vol: 133, Pages: 1472-1478, ISSN: 0022-202X
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- Citations: 15
Dominguez-Huettinger E, Ono M, Barahona M, et al., 2013, Risk factor-dependent dynamics of atopic dermatitis: modelling multi-scale regulation of epithelium homeostasis, INTERFACE FOCUS, Vol: 3, ISSN: 2042-8898
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- Citations: 11
Furmanski AL, Saldana JI, Ono M, et al., 2013, Tissue-Derived Hedgehog Proteins Modulate Th Differentiation and Disease, JOURNAL OF IMMUNOLOGY, Vol: 190, Pages: 2641-2649, ISSN: 0022-1767
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- Citations: 68
Ono M, Tanaka RJ, Kano M, et al., 2013, Visualising the Cross-Level Relationships between Pathological and Physiological Processes and Gene Expression: Analyses of Haematological Diseases, PLOS ONE, Vol: 8, ISSN: 1932-6203
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- Citations: 8
Huettinger ED, Ono M, Barahona M, et al., 2012, Mathematical model of the development of Atopic dermatitis, 22nd IUBMB Congress/37th FEBS Congress, Publisher: WILEY-BLACKWELL, Pages: 523-523, ISSN: 1742-464X
Dominguez-Huttinger E, Ono M, Barahona M, et al., 2012, System-level investigation of risk factors for atopic dermatitis by mathematical modelling and analysis, 42nd Annual Meeting of the European-Society-for-Dermatological-Research (ESDR), Publisher: NATURE PUBLISHING GROUP, Pages: S25-S25, ISSN: 0022-202X
Yoshioka Y, Ono M, Osaki M, et al., 2012, Differential effects of inhibition of bone morphogenic protein (BMP) signalling on T-cell activation and differentiation, EUROPEAN JOURNAL OF IMMUNOLOGY, Vol: 42, Pages: 749-759, ISSN: 0014-2980
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- Citations: 48
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