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Ethan shevach

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https://www.readbyqxmd.com/read/27880974/deep-sequencing-of-the-tcrb-repertoire-of-human-foxp3-and-foxp3-t-cells-suggests-that-they-are-completely-distinct-and-non-overlapping
#1
Amit Golding, Samuel Darko, William H Wylie, Daniel C Douek, Ethan M Shevach
Maintenance of peripheral tolerance requires a balance between auto-reactive conventional T cells (Tconv) and thymically-derived Foxp3(+) regulatory T cells (tTregs). Considerable controversy exists regarding the similarities/differences in TCR repertoires expressed by Tconv and tTregs. We generated highly purified populations of human adult and cord blood Tconv and tTregs based on the differential expression of CD25 and CD127. The purity of the sorted populations was validated by intracellular staining for Foxp3 and Helios...
November 23, 2016: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/27439517/a-simple-versatile-antibody-based-barcoding-method-for-flow-cytometry
#2
Billur Akkaya, Pietro Miozzo, Amanda H Holstein, Ethan M Shevach, Susan K Pierce, Munir Akkaya
Barcoding of biological samples is a commonly used strategy to mark or identify individuals within a complex mixture. However, cell barcoding has not yet found wide use in flow cytometry that would benefit greatly from the ability to analyze pooled experimental samples simultaneously. This is due, in part, to technical and practical limitations of current fluorescent dye-based methods. In this study, we describe a simple, versatile barcoding strategy that relies on combinations of a single Ab conjugated to different fluorochromes and thus in principle can be integrated into any flow cytometry application...
September 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27366791/cardiac-myosin-th17-responses-promote-heart-failure-in-human-myocarditis
#3
Jennifer M Myers, Leslie T Cooper, David C Kem, Stavros Stavrakis, Stanley D Kosanke, Ethan M Shevach, DeLisa Fairweather, Julie A Stoner, Carol J Cox, Madeleine W Cunningham
In human myocarditis and its sequela dilated cardiomyopathy (DCM), the mechanisms and immune phenotype governing disease and subsequent heart failure are not known. Here, we identified a Th17 cell immunophenotype of human myocarditis/DCM with elevated CD4(+)IL17(+) T cells and Th17-promoting cytokines IL-6, TGF-β, and IL-23 as well as GM-CSF-secreting CD4(+) T cells. The Th17 phenotype was linked with the effects of cardiac myosin on CD14(+) monocytes, TLR2, and heart failure. Persistent heart failure was associated with high percentages of IL-17-producing T cells and IL-17-promoting cytokines, and the myocarditis/DCM phenotype included significantly low percentages of FOXP3(+) Tregs, which may contribute to disease severity...
June 16, 2016: JCI Insight
https://www.readbyqxmd.com/read/27062243/the-garp-latent-tgf-%C3%AE-1-complex-on-treg-cells-modulates-the-induction-of-peripherally-derived-treg-cells-during-oral-tolerance
#4
Justin P Edwards, Timothy W Hand, Denise Morais da Fonseca, Deborah D Glass, Yasmine Belkaid, Ethan M Shevach
Treg cells can secrete latent TGF-β1 (LTGF-β1), but can also utilize an alternative pathway for transport and expression of LTGF-β1 on the cell surface in which LTGF-β1 is coupled to a distinct LTGF-β binding protein termed glycoprotein A repetitions predominant (GARP)/LRRC32. The function of the GARP/LTGF-β1 complex has remained elusive. Here, we examine in vivo the roles of GARP and TGF-β1 in the induction of oral tolerance. When Foxp3(-) OT-II T cells were transferred to wild-type recipient mice followed by OVA feeding, the conversion of Foxp3(-) to Foxp3(+) OT-II cells was dependent on recipient Treg cells...
June 2016: European Journal of Immunology
https://www.readbyqxmd.com/read/26773142/%C3%AE-%C3%AE-t-cells-protect-the-liver-and-lungs-of-mice-from-autoimmunity-induced-by-scurfy-lymphocytes
#5
Hideyuki Ujiie, Ethan M Shevach
γδ T cells have been shown to have immunoregulatory functions in several experimental autoimmune models. A mutation of the Foxp3 gene leads to the absence of regulatory T cells (Tregs) and a fatal systemic autoimmune disease in scurfy mice. Transfer of scurfy lymphocytes to RAG deficient (RAG(-/-)) recipients reproduces the inflammatory phenotype of the scurfy donor, including hepatitis and pneumonitis. In this study, we show that TCRα(-/-) recipients, which lack αβ T cells but have γδ T cells and B cells, are significantly protected from the hepatitis and pneumonitis, but not the dermatitis, induced by adoptive transfer of scurfy lymphocytes...
February 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/26686412/transcriptome-profiling-of-human-foxp3-regulatory-t-cells
#6
Ravikiran Bhairavabhotla, Yong C Kim, Deborah D Glass, Thelma M Escobar, Mira C Patel, Rami Zahr, Cuong K Nguyen, Gokhul K Kilaru, Stefan A Muljo, Ethan M Shevach
The major goal of this study was to perform an in depth characterization of the "gene signature" of human FoxP3(+) T regulatory cells (Tregs). Highly purified Tregs and T conventional cells (Tconvs) from multiple healthy donors (HD), either freshly explanted or activated in vitro, were analyzed via RNA sequencing (RNA-seq) and gene expression changes validated using the nCounter system. Additionally, we analyzed microRNA (miRNA) expression using TaqMan low-density arrays. Our results confirm previous studies demonstrating selective gene expression of FoxP3, IKZF2, and CTLA4 in Tregs...
February 2016: Human Immunology
https://www.readbyqxmd.com/read/26582951/helios-controls-a-limited-subset-of-regulatory-t-cell-functions
#7
Mathew Sebastian, Maria Lopez-Ocasio, Amina Metidji, Sadiye Amcaoglu Rieder, Ethan M Shevach, Angela M Thornton
A subpopulation (60-70%) of Foxp3(+) regulatory T cells (Tregs) in both mouse and man expresses the transcription factor Helios, but its role in Treg function is still unknown. We generated Treg-specific Helios-deficient mice to examine the function of Helios in Tregs. We show that the selective deletion of Helios in Tregs leads to slow, progressive systemic immune activation, hypergammaglobulinemia, and enhanced germinal center formation in the absence of organ-specific autoimmunity. Helios-deficient Treg suppressor function was normal in vitro, as well as in an in vivo inflammatory bowel disease model...
January 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/26580498/william-e-paul-1936-2015
#8
Ethan M Shevach, David H Margulies
No abstract text is available yet for this article.
December 2015: Nature Immunology
https://www.readbyqxmd.com/read/26122357/monitoring-regulatory-t-cells-in-clinical-samples-consensus-on-an-essential-marker-set-and-gating-strategy-for-regulatory-t-cell-analysis-by-flow-cytometry
#9
Saskia J A M Santegoets, Eveline M Dijkgraaf, Alessandra Battaglia, Philipp Beckhove, Cedrik M Britten, Awen Gallimore, Andrew Godkin, Cecile Gouttefangeas, Tanja D de Gruijl, Hans J P M Koenen, Alexander Scheffold, Ethan M Shevach, Janet Staats, Kjetil Taskén, Theresa L Whiteside, Judith R Kroep, Marij J P Welters, Sjoerd H van der Burg
Regulatory T cell (Treg)-mediated immunosuppression is considered a major obstacle for successful cancer immunotherapy. The association between clinical outcome and Tregs is being studied extensively in clinical trials, but unfortunately, no consensus has been reached about (a) the markers and (b) the gating strategy required to define human Tregs in this context, making it difficult to draw final conclusions. Therefore, we have organized an international workshop on the detection and functional testing of Tregs with leading experts in the field, and 40 participants discussing different analyses and the importance of different markers and context in which Tregs were analyzed...
October 2015: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/26062998/eos-is-redundant-for-regulatory-t-cell-function-but-plays-an-important-role-in-il-2-and-th17-production-by-cd4-conventional-t-cells
#10
Sadiye Amcaoglu Rieder, Amina Metidji, Deborah Dacek Glass, Angela M Thornton, Tohru Ikeda, Bruce A Morgan, Ethan M Shevach
Eos belongs to the Ikaros family of transcription factors. It was reported to be a regulatory T cell (Treg) signature gene, to play a critical role in Treg suppressor functions, and to maintain Treg stability. We used mice with a global deficiency in Eos to re-examine the role of Eos expression in both Tregs and conventional T cells (Tconvs). Tregs from Eos-deficient (Eos(-/-)) mice developed normally, displayed a normal Treg phenotype, and exhibited normal suppressor function in vitro. Eos(-/-) Tregs were as effective as Tregs from wild-type (WT) mice in suppressing inflammation in a model of inflammatory bowel disease...
July 15, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/25795758/ifn-%C3%AE-%C3%AE-receptor-signaling-promotes-regulatory-t-cell-development-and-function-under-stress-conditions
#11
Amina Metidji, Sadiye Amcaoglu Rieder, Deborah Dacek Glass, Isabelle Cremer, George A Punkosdy, Ethan M Shevach
Type I IFNs are a family of cytokines with antiviral and immunomodulatory properties. Although the antiviral effects of IFNs are well characterized, their immunomodulatory properties are less clear. To specifically address the effects of type I IFNs on T regulatory cells (Tregs), we studied mixed bone marrow chimeras between wild-type and IFN-α/β receptor (IFNAR) knockout (KO) mice, and heterozygous female mice expressing a Treg-specific deletion of the IFNAR. In these two models, IFNAR signaling promotes the development of the Treg lineage in the thymus and their survival in the periphery...
May 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/25762785/coexpression-of-tigit-and-fcrl3-identifies-helios-human-memory-regulatory-t-cells
#12
Khalid Bin Dhuban, Eva d'Hennezel, Emil Nashi, Amit Bar-Or, Sadiye Rieder, Ethan M Shevach, Satoshi Nagata, Ciriaco A Piccirillo
Two distinct subsets of CD4(+)Foxp3(+) regulatory T (Treg) cells have been described based on the differential expression of Helios, a transcription factor of the Ikaros family. Efforts to understand the origin and biological roles of these Treg populations in regulating immune responses have, however, been hindered by the lack of reliable surface markers to distinguish and isolate them for subsequent functional studies. Using a single-cell cloning strategy coupled with microarray analysis of different Treg functional subsets in humans, we identify the mRNA and protein expression of TIGIT and FCRL3 as a novel surface marker combination that distinguishes Helios(+)FOXP3(+) from Helios(-)FOXP3(+) memory cells...
April 15, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/25498909/engineered-antigen-specific-human-regulatory-t-cells-immunosuppression-of-fviii-specific-t-and-b-cell-responses
#13
Yong Chan Kim, Ai-Hong Zhang, Yan Su, Sadiye Amcaoglu Rieder, Robert J Rossi, Ruth A Ettinger, Kathleen P Pratt, Ethan M Shevach, David W Scott
Expansion of human regulatory T cells (Tregs) for clinical applications offers great promise for the treatment of undesirable immune responses in autoimmunity, transplantation, allergy, and antidrug antibody responses, including inhibitor responses in hemophilia A patients. However, polyclonal Tregs are nonspecific and therefore could potentially cause global immunosuppression. To avoid this undesirable outcome, the generation of antigen-specific Tregs would be advantageous. Herein, we report the production and properties of engineered antigen-specific Tregs, created by transduction of a recombinant T-cell receptor obtained from a hemophilia A subject's T-cell clone, into expanded human FoxP3(+) Tregs...
February 12, 2015: Blood
https://www.readbyqxmd.com/read/25492937/foxp3-mediated-inhibition-of-akt-inhibits-glut1-glucose-transporter-1-expression-in-human-t-regulatory-cells
#14
Samik Basu, Britany Hubbard, Ethan M Shevach
CD4(+)CD25(+)Foxp3(+) Tregs have a diminished capacity to activate the PI3K/Akt pathway. Although blunted Akt activity is necessary to maintain Treg function, the consequences of this altered signaling are unclear. Glut1 is a cell-surface receptor responsible for facilitating glucose transport across plasma membranes, whose expression is tightly coupled to costimulatory signals and Akt phosphorylation. Freshly isolated human Tregs were unable to up-regulate Glut1 in response to TCR and costimulatory signals compared with Tconv...
February 2015: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/25329180/tcr-signaling-fuels-t-reg-cell-suppressor-function
#15
COMMENT
Jinfang Zhu, Ethan M Shevach
No abstract text is available yet for this article.
November 2014: Nature Immunology
https://www.readbyqxmd.com/read/25127859/release-of-active-tgf-%C3%AE-1-from-the-latent-tgf-%C3%AE-1-garp-complex-on-t-regulatory-cells-is-mediated-by-integrin-%C3%AE-8
#16
Justin P Edwards, Angela M Thornton, Ethan M Shevach
Activated T regulatory cells (Tregs) express latent TGF-β1 on their cell surface bound to GARP. Although integrins have been implicated in mediating the release of active TGF-β1 from the complex of latent TGF-β1 and latent TGF-β1 binding protein, their role in processing latent TGF-β1 from the latent TGF-β1/GARP complex is unclear. Mouse CD4(+)Foxp3(+) Treg, but not CD4(+)Foxp3(-) T cells, expressed integrin β8 (Itgb8) as detected by quantitative RT-PCR. Itgb8 expression was a marker of thymically derived (t)Treg, because it could not be detected on Foxp3(+)Helios(-) Tregs or on Foxp3(+) T cells induced in vitro...
September 15, 2014: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/24712461/ttregs-ptregs-and-itregs-similarities-and-differences
#17
REVIEW
Ethan M Shevach, Angela M Thornton
Foxp3(+) T-regulatory cells (Tregs) are primarily generated in the thymus (tTreg), but also may be generated extrathymically at peripheral sites (pTreg), or induced in cell culture (iTreg) in the presence of transforming growth factor β (TGFβ). A major unresolved issue is how these different populations of Tregs exert their suppressive function in vivo. We have developed novel systems in which the function of Tregs can be evaluated in vivo in normal mice. Our studies demonstrate that one prominent mechanism of action of polyclonal tTregs is to inhibit T-effector cell trafficking to the target organ, while antigen-specific iTregs primarily prevent T-cell priming by acting on antigen-presenting dendritic cells (DCs)...
May 2014: Immunological Reviews
https://www.readbyqxmd.com/read/24324930/endogenous-mouse-mammary-tumor-viruses-mtv-new-roles-for-an-old-virus-in-cancer-infection-and-immunity
#18
REVIEW
Michael P Holt, Ethan M Shevach, George A Punkosdy
Mouse Mammary Tumor Viruses are beta-retroviruses that exist in both exogenous (MMTV) and endogenous (Mtv) forms. Exogenous MMTV is transmitted via the milk of lactating animals and is capable of inducing mammary gland tumors later in life. MMTV has provided a number of critical models for studying both viral infection as well as human breast cancer. In addition to the horizontally transmitted MMTV, most inbred mouse strains contain permanently integrated Mtv proviruses within their genome that are remnants of MMTV infection and vertically transmitted...
2013: Frontiers in Oncology
https://www.readbyqxmd.com/read/24218453/antigen-specific-induced-t-regulatory-cells-impair-dendritic-cell-function-via-an-il-10-march1-dependent-mechanism
#19
Gouri Chattopadhyay, Ethan M Shevach
Foxp3(+) T regulatory cells (Tregs) are critically important for the maintenance of immunological tolerance, immune homeostasis, and prevention of autoimmunity. Dendritic cells (DCs) are one of the major targets of Treg-mediated suppression. Some studies have suggested that Treg-mediated suppression of DC function is mediated by the interaction of CTLA-4 on Tregs with CD80/CD86 on the DCs resulting in downregulation of CD80/CD86 expression and a decrease in costimulation. We have re-examined the effects of Tregs on mouse DC function in a model in which Ag-specific, induced Tregs (iTregs) are cocultured with DCs in the absence of T effector cells...
December 15, 2013: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/23925905/the-percentage-of-foxp3-helios-treg-cells-correlates-positively-with-disease-activity-in-systemic-lupus-erythematosus
#20
Amit Golding, Sarfaraz Hasni, Gabor Illei, Ethan M Shevach
OBJECTIVE: To assess the use of Helios in combination with FoxP3 as a superior method for identifying non-cytokine-producing human Treg cells in patients with systemic lupus erythematosus (SLE) and to determine if FoxP3+Helios+ Treg cells are maintained at normal levels in patients with clinically active disease. METHODS: Peripheral blood mononuclear cells (PBMCs) were purified from the blood of healthy volunteer donors and from 52 consecutive patients with SLE of varying clinical activity (Systemic Lupus Erythematosus Disease Activity Index scores of 0, 2-4, and ≥ 5)...
November 2013: Arthritis and Rheumatism
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