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Richard a flavell

Tianxia Guan, Claudia X Dominguez, Robert A Amezquita, Brian J Laidlaw, Jijun Cheng, Jorge Henao-Mejia, Adam Williams, Richard A Flavell, Jun Lu, Susan M Kaech
Long-term immunity depends partly on the establishment of memory CD8 + T cells. We identified a counterregulatory network between the homologous transcription factors ZEB1 and ZEB2 and the miR-200 microRNA family, which modulates effector CD8 + T cell fates. Unexpectedly, Zeb1 and Zeb2 had reciprocal expression patterns and were functionally uncoupled in CD8 + T cells. ZEB2 promoted terminal differentiation, whereas ZEB1 was critical for memory T cell survival and function. Interestingly, the transforming growth factor β (TGF-β) and miR-200 family members, which counterregulate the coordinated expression of Zeb1 and Zeb2 during the epithelial-to-mesenchymal transition, inversely regulated Zeb1 and Zeb2 expression in CD8 + T cells...
February 15, 2018: Journal of Experimental Medicine
Russell D C Bicknell, Ada J Klinkhamer, Richard J Flavel, Stephen Wroe, John R Paterson
Limulus polyphemus, an archetypal chelicerate taxon, has interested both biological and paleontological researchers due to its unique suite of anatomical features and as a useful modern analogue for fossil arthropod groups. To assist the study and documentation of this iconic taxon, we present a 3D atlas on the appendage musculature, with specific focus on the muscles of the cephalothoracic appendages. As L. polyphemus appendage musculature has been the focus of extensive study, depicting the muscles in 3D will facilitate a more complete understanding thereof for future researchers...
2018: PloS One
Xu Zhou, Ruth A Franklin, Miri Adler, Jeremy B Jacox, Will Bailis, Justin A Shyer, Richard A Flavell, Avi Mayo, Uri Alon, Ruslan Medzhitov
Cell communication within tissues is mediated by multiple paracrine signals including growth factors, which control cell survival and proliferation. Cells and the growth factors they produce and receive constitute a circuit with specific properties that ensure homeostasis. Here, we used computational and experimental approaches to characterize the features of cell circuits based on growth factor exchange between macrophages and fibroblasts, two cell types found in most mammalian tissues. We found that the macrophage-fibroblast cell circuit is stable and robust to perturbations...
January 30, 2018: Cell
Johanna Sophie Alfen, Paola Larghi, Federica Facciotti, Nicola Gagliani, Roberto Bosotti, Moira Paroni, Stefano Maglie, Paola Gruarin, Chiara Maria Vasco, Valeria Ranzani, Cristina Frusteri, Andrea Iseppon, Monica Moro, Maria Cristina Crosti, Stefano Gatti, Massimiliano Pagani, Flavio Caprioli, Sergio Abrignani, Richard A Flavell, Jens Geginat
BACKGROUND: IL-10 is an anti-inflammatory cytokine that is required for intestinal immune homeostasis. It mediates suppression of T-cell responses by type-1 regulatory (Tr1-) cells, but is also produced by CD25+ Tregs. OBJECTIVE: We aimed to identify and characterize human intestinal Tr1-cells, and to investigate if they are a relevant cellular source of IL-10 in inflammatory bowel diseases (IBDs). METHODS: CD4+T-cells isolated from the intestinal lamina propria of humans and mice were analyzed for phenotype, cytokine production and suppressive capacities...
January 21, 2018: Journal of Allergy and Clinical Immunology
Johanna Emgård, Hana Kammoun, Bethania García-Cassani, Julie Chesné, Sara M Parigi, Jean-Marie Jacob, Hung-Wei Cheng, Elza Evren, Srustidhar Das, Paulo Czarnewski, Natalie Sleiers, Felipe Melo-Gonzalez, Egle Kvedaraite, Mattias Svensson, Elke Scandella, Matthew R Hepworth, Samuel Huber, Burkhard Ludewig, Lucie Peduto, Eduardo J Villablanca, Henrique Veiga-Fernandes, João P Pereira, Richard A Flavell, Tim Willinger
Group 3 innate lymphoid cells (ILC3s) sense environmental signals and are critical for tissue integrity in the intestine. Yet, which signals are sensed and what receptors control ILC3 function remain poorly understood. Here, we show that ILC3s with a lymphoid-tissue-inducer (LTi) phenotype expressed G-protein-coupled receptor 183 (GPR183) and migrated to its oxysterol ligand 7α,25-hydroxycholesterol (7α,25-OHC). In mice lacking Gpr183 or 7α,25-OHC, ILC3s failed to localize to cryptopatches (CPs) and isolated lymphoid follicles (ILFs)...
January 16, 2018: Immunity
Jiyu Tong, Guangchao Cao, Ting Zhang, Esen Sefik, Maria Carolina Amezcua Vesely, James P Broughton, Shu Zhu, Huabin Li, Bin Li, Lei Chen, Howard Y Chang, Bing Su, Richard A Flavell, Hua-Bing Li
No abstract text is available yet for this article.
January 5, 2018: Cell Research
Eric J C Gálvez, Aida Iljazovic, Achim Gronow, Richard Flavell, Till Strowig
Contradicting observations have been made regarding the relative contributions of immune sensors to shaping the microbiome, yet the reasons for these discrepancies are not fully understood. Here, we investigated the contribution of environmental factors in shaping the microbiome in mice deficient in adaptive immunity (Rag2-/-) and Nlrp6, an immune sensor proposed to be involved in regulation of microbiota composition. In conventionally housed Nlrp6-/- mice, familial transmission has a significant effect on microbiota composition, complicating the analysis of genotype-dependent effects...
December 26, 2017: Cell Reports
Etienne Humblin, Marion Thibaudin, Fanny Chalmin, Valentin Derangère, Emeric Limagne, Corentin Richard, Richard A Flavell, Sandy Chevrier, Sylvain Ladoire, Hélène Berger, Romain Boidot, Lionel Apetoh, Frédérique Végran, François Ghiringhelli
Interferon regulatory factors (IRF) have critical functions in lymphoid development and in immune response regulation. Although many studies have described the function of IRF4 in CD4+ T cells, few have focused on the IRF4 homologue, IRF8. Here, we show that IRF8 is required for Th9 differentiation in vitro and in vivo. IRF8 functions through a transcription factor complex consisting of IRF8, IRF4, PU.1 and BATF, which binds to DNA and boosts Il9 transcription. By contrast, IRF8 deficiency promotes the expression of other genes such as Il4, as IRF8 dimerises with the transcriptional repressor ETV6 and inhibits Il4 expression...
December 12, 2017: Nature Communications
Anthony Rongvaux, Tim Willinger, Jan Martinek, Till Strowig, Sofia V Gearty, Lino L Teichmann, Yasuyuki Saito, Florentina Marches, Stephanie Halene, A Karolina Palucka, Markus G Manz, Richard A Flavell
No abstract text is available yet for this article.
December 8, 2017: Nature Biotechnology
Nan Guo Ring, Dietmar Herndler-Brandstetter, Kipp Weiskopf, Liang Shan, Jens-Peter Volkmer, Benson M George, Melanie Lietzenmayer, Kelly M McKenna, Tejaswitha J Naik, Aaron McCarty, Yunjiang Zheng, Aaron M Ring, Richard A Flavell, Irving L Weissman
Cancer immunotherapy has emerged as a promising therapeutic intervention. However, complete and durable responses are only seen in a fraction of patients who have cancer. A key factor that limits therapeutic success is the infiltration of tumors by cells of the myeloid lineage. The inhibitory receptor signal regulatory protein-α (SIRPα) is a myeloid-specific immune checkpoint that engages the "don't eat me" signal CD47 expressed on tumors and normal tissues. We therefore developed the monoclonal antibody KWAR23, which binds human SIRPα with high affinity and disrupts its binding to CD47...
December 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
Hua Yu, Ricardo Paiva, Richard A Flavell
Type 1 diabetes (T1D) is a T-cell-mediated autoimmune disease resulting in islet β-cell destruction, hypoinsulinaemia and severely altered glucose homeostasis. Although the mechanisms that initiate T1D still remain elusive, a breakdown of immune tolerance between effector T-cells (Teff ) and regulatory T-cells (Treg ) is considered to be the crucial component leading to autoimmunity. As such, strategies have been developed to boost the number and/or function of Treg in the hope of specifically hampering the pathogenic Teff activity...
February 2018: Immunology
Dörte Kleinschmidt, Anastasios D Giannou, Heather M McGee, Jan Kempski, Babett Steglich, Francis Jessica Huber, Thomas Michael Ernst, Ahmad Mustafa Shiri, Claudia Wegscheid, Elena Tasika, Peter Hübener, Philipp Huber, Tanja Bedke, Niklas Steffens, Theodora Agalioti, Tobias Fuchs, Jill Noll, Hannelore Lotter, Gisa Tiegs, Ansgar W Lohse, Jonathan H Axelrod, Eithan Galun, Richard A Flavell, Nicola Gagliani, Samuel Huber
Acute liver injury can be secondary to a variety of causes, including infections, intoxication, and ischemia. All of these insults induce hepatocyte death and subsequent inflammation, which can make acute liver injury a life-threatening event. IL-22 is a dual natured cytokine which has context-dependent protective and pathogenic properties during tissue damage. Accordingly, IL-22 was shown to promote liver regeneration upon acute liver damage. However, other studies suggest pathogenic properties of IL-22 during chronic liver injury...
December 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
Dietmar Herndler-Brandstetter, Liang Shan, Yi Yao, Carmen Stecher, Valerie Plajer, Melanie Lietzenmayer, Till Strowig, Marcel R de Zoete, Noah W Palm, Jie Chen, Catherine A Blish, Davor Frleta, Cagan Gurer, Lynn E Macdonald, Andrew J Murphy, George D Yancopoulos, Ruth R Montgomery, Richard A Flavell
Immunodeficient mice reconstituted with a human immune system represent a promising tool for translational research as they may allow modeling and therapy of human diseases in vivo. However, insufficient development and function of human natural killer (NK) cells and T cell subsets limit the applicability of humanized mice for studying cancer biology and therapy. Here, we describe a human interleukin 15 ( IL15 ) and human signal regulatory protein alpha ( SIRPA ) knock-in mouse on a Rag2-/- Il2rg-/- background (SRG-15)...
November 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
Urmi Roy, Eric J C Gálvez, Aida Iljazovic, Till Robin Lesker, Adrian J Błażejewski, Marina C Pils, Ulrike Heise, Samuel Huber, Richard A Flavell, Till Strowig
Inflammatory bowel disease comprises a group of heterogeneous diseases characterized by chronic and relapsing mucosal inflammation. Alterations in microbiota composition have been proposed to contribute to disease development, but no uniform signatures have yet been identified. Here, we compare the ability of a diverse set of microbial communities to exacerbate intestinal inflammation after chemical damage to the intestinal barrier. Strikingly, genetically identical wild-type mice differing only in their microbiota composition varied strongly in their colitis susceptibility...
October 24, 2017: Cell Reports
Liang Shan, Kai Deng, Hongbo Gao, Sifei Xing, Adam A Capoferri, Christine M Durand, S Alireza Rabi, Gregory M Laird, Michelle Kim, Nina N Hosmane, Hung-Chih Yang, Hao Zhang, Joseph B Margolick, Linghua Li, Weiping Cai, Ruian Ke, Richard A Flavell, Janet D Siliciano, Robert F Siliciano
The latent reservoir for HIV-1 in resting memory CD4(+) T cells is the major barrier to curing HIV-1 infection. Studies of HIV-1 latency have focused on regulation of viral gene expression in cells in which latent infection is established. However, it remains unclear how infection initially becomes latent. Here we described a unique set of properties of CD4(+) T cells undergoing effector-to-memory transition including temporary upregulation of CCR5 expression and rapid downregulation of cellular gene transcription...
October 17, 2017: Immunity
Shashi Kant, Claire L Standen, Caroline Morel, Dae Young Jung, Jason K Kim, Wojciech Swat, Richard A Flavell, Roger J Davis
Obesity is a major risk factor for the development of metabolic syndrome and type 2 diabetes. How obesity contributes to metabolic syndrome is unclear. Free fatty acid (FFA) activation of a non-receptor tyrosine kinase (SRC)-dependent cJun NH2-terminal kinase (JNK) signaling pathway is implicated in this process. However, the mechanism that mediates SRC-dependent JNK activation is unclear. Here, we identify a role for the scaffold protein JIP1 in SRC-dependent JNK activation. SRC phosphorylation of JIP1 creates phosphotyrosine interaction motifs that bind the SH2 domains of SRC and the guanine nucleotide exchange factor VAV...
September 19, 2017: Cell Reports
Walter K Mowel, Sam J McCright, Jonathan J Kotzin, Magalie A Collet, Asli Uyar, Xin Chen, Alexandra DeLaney, Sean P Spencer, Anthony T Virtue, EnJun Yang, Alejandro Villarino, Makoto Kurachi, Margaret C Dunagin, Gretchen Harms Pritchard, Judith Stein, Cynthia Hughes, Diogo Fonseca-Pereira, Henrique Veiga-Fernandes, Arjun Raj, Taku Kambayashi, Igor E Brodsky, John J O'Shea, E John Wherry, Loyal A Goff, John L Rinn, Adam Williams, Richard A Flavell, Jorge Henao-Mejia
Commitment to the innate lymphoid cell (ILC) lineage is determined by Id2, a transcriptional regulator that antagonizes T and B cell-specific gene expression programs. Yet how Id2 expression is regulated in each ILC subset remains poorly understood. We identified a cis-regulatory element demarcated by a long non-coding RNA (lncRNA) that controls the function and lineage identity of group 1 ILCs, while being dispensable for early ILC development and homeostasis of ILC2s and ILC3s. The locus encoding this lncRNA, which we termed Rroid, directly interacted with the promoter of its neighboring gene, Id2, in group 1 ILCs...
September 19, 2017: Immunity
Thaiz Rivera Vargas, Zhijian Cai, Yingying Shen, Magalie Dosset, Isis Benoit-Lizon, Tiffany Martin, Aurélie Roussey, Richard A Flavell, François Ghiringhelli, Lionel Apetoh
Autophagy, a catabolic mechanism that involves degradation of cellular components, is essential for cell homeostasis. Although autophagy favours the lineage stability of regulatory T cells, the contribution of autophagy to the differentiation of effector CD4 T cells remains unclear. Here we show that autophagy selectively represses T helper 9 (TH 9) cell differentiation. CD4 T cells lacking Atg3 or Atg5 have increased interleukin-9 (IL-9) expression upon differentiation into TH 9 cells relative to Atg3- or Atg5-expressing control cells...
September 15, 2017: Nature Communications
Will Bailis, Justin A Shyer, Michael Chiorazzi, Richard A Flavell
The tumor microenvironment presents metabolic constraints to immunosurveiling cells. In this issue of Cancer Cell, Zhang et al. demonstrate that CD8+ TILs reprogram under hypoxic and hypoglycemic conditions, regaining effector function by engaging fatty acid catabolism, which is promoted by fenofibrate and synergistic with immune checkpoint blockade therapy.
September 11, 2017: Cancer Cell
Hua Yu, Nicola Gagliani, Harumichi Ishigame, Samuel Huber, Shu Zhu, Enric Esplugues, Kevan C Herold, Li Wen, Richard A Flavell
Growing insight into the pathogenesis of autoimmune diseases and numerous studies in preclinical models highlights the potential of regulatory T cells to restore tolerance. By using non-obese diabetic (NOD) BDC2.5 TCR-transgenic (Tg), and IL-10 and Foxp3 double-reporter mice, we demonstrate that alteration of gut microbiota during cohousing experiments or treatment with anti-CD3 mAb significantly increase intestinal IL-10-producing type 1 regulatory T (Tr1) cells and decrease diabetes incidence. These intestinal antigen-specific Tr1 cells have the ability to migrate to the periphery via a variety of chemokine receptors such as CCR4, CCR5, and CCR7 and to suppress proliferation of Th1 cells in the pancreas...
September 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
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