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Ethan shevach

Arunakumar Gangaplara, Craig Martens, Eric Dahlstrom, Amina Metidji, Ameya S Gokhale, Deborah D Glass, Maria Lopez-Ocasio, Rachel Baur, Kishore Kanakabandi, Stephen F Porcella, Ethan M Shevach
Regulatory T cells (Tregs) play a cardinal role in the immune system by suppressing detrimental autoimmune responses, but their role in acute, chronic infectious diseases and tumor microenvironment remains unclear. We recently demonstrated that IFN-α/β receptor (IFNAR) signaling promotes Treg function in autoimmunity. Here we dissected the functional role of IFNAR-signaling in Tregs using Treg-specific IFNAR deficient (IFNARfl/flxFoxp3YFP-Cre) mice in acute LCMV Armstrong, chronic Clone-13 viral infection, and in tumor models...
April 19, 2018: PLoS Pathogens
Elien Vermeersch, Frederik Denorme, Wim Maes, Simon F De Meyer, Karen Vanhoorelbeke, Justin Edwards, Ethan M Shevach, Derya Unutmaz, Hodaka Fujii, Hans Deckmyn, Claudia Tersteeg
BACKGROUND: Glycoprotein-A Repetitions Predominant protein (GARP or LRRC32) is present on among others human platelets and endothelial cells. Evidence for its involvement in thrombus formation was suggested by full knockout of GARP in zebrafish. OBJECTIVES: To evaluate the role of GARP in platelet physiology and in thrombus formation using platelet and endothelial conditional GARP knock out mice. METHODS: Platelet and endothelial specific GARP knockout mice were generated using the Cre-loxP recombination system...
2017: PloS One
Michael P Holt, George A Punkosdy, Deborah D Glass, Ethan M Shevach
Foxp3+ T regulatory cells (Tregs), conventional CD4+ Foxp3- T cells, and CD8+ T cells represent heterogeneous populations composed of naive phenotype (NP, CD44low ) and memory phenotype (MP, CD44high ) subpopulations. NP and MP subsets differ in their activation state, contribution to immune function, and capacity to proliferate in vivo. To further understand the factors that contribute to the differential homeostasis of NP/MP subsets, we examined the differential effects of CD28 and CTLA-4 interaction with CD80/CD86, as well as MHC class II-TCR interaction within mouse Treg pools and CD4+ and CD8+ T cell pools...
February 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
Ethan M Shevach
Foxp3(+) T regulatory cells (Tregs) play critical roles in immune homeostasis primarily by suppressing many aspects of the immune response. Tregs uniquely express GARP on their cell surface and GARP functions as a delivery system for latent TGF-β. As Treg-derived TGF-β may mediate the suppressive functions of Tregs, GARP may represent a target to inhibit Treg suppression in cancer or augment suppression in autoimmunity. Areas covered: This article will focus on 1) the role of Treg-derived TGF-β in the suppressive activity of Treg, 2) the cellular and molecular regulation of expression of GARP on mouse and human Tregs, 3) the role of integrins in the activation of latent-TGF-β/GARP complex, 4) an overview of our present understanding of the function of the latent-TGF-β/GARP complex...
February 2017: Expert Opinion on Therapeutic Targets
Billur Akkaya, Amanda H Holstein, Christopher Isaac, Mitra P Maz, Deborah D Glass, Ethan M Shevach, Munir Akkaya
Ex-vivo differentiation of regulatory T cells (Tregs) from naïve CD4(+) T-cells has been widely used in immunological research. Isolation of a highly pure naïve T cell population is the key factor that determines the efficiency of subsequent Treg differentiation. Currently, this step relies mostly on FACS sorting, which is often costly, time consuming, and inconvenient. Alternatively, magnetic separation of T-cells can be performed; yet, available protocols fail to reach sort level purity and consequently result in low Treg differentiation efficiency...
February 2017: Journal of Immunological Methods
A Golding, S Darko, W H Wylie, D C Douek, E M Shevach
Maintenance of peripheral tolerance requires a balance between autoreactive conventional T cells (Tconv ) and thymically derived forkhead box protein 3 (FoxP3)(+) regulatory T cells (tTregs ). Considerable controversy exists regarding the similarities/differences in T cell receptor (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...
April 2017: Clinical and Experimental Immunology
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
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
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
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
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
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
Ethan M Shevach, David H Margulies
No abstract text is available yet for this article.
December 2015: Nature Immunology
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
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
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
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
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
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
Jinfang Zhu, Ethan M Shevach
No abstract text is available yet for this article.
November 2014: Nature Immunology
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