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  • MAIT cell activation and dynamics associated with COVID-19 disease severity
    Sci. Immunol (IF 13.44) Pub Date : 2020-09-28
    Tiphaine Parrot, Jean-Baptiste Gorin, Andrea Ponzetta, Kimia T. Maleki, Tobias Kammann, Johanna Emgård, André Perez-Potti, Takuya Sekine, Olga Rivera-Ballesteros, the Karolinska COVID-19 Study Group†, Sara Gredmark-Russ, Olav Rooyackers, Elin Folkesson, Lars I. Eriksson, Anna Norrby-Teglund, Hans-Gustaf Ljunggren, Niklas K. Björkström, Soo Aleman, Marcus Buggert, Jonas Klingström, Kristoffer Strålin

    Severe COVID-19 is characterized by excessive inflammation of the lower airways. The balance of protective versus pathological immune responses in COVID-19 is incompletely understood. Mucosa-associated invariant T (MAIT) cells are antimicrobial T cells that recognize bacterial metabolites, and can also function as innate-like sensors and mediators of antiviral responses. Here, we investigated the MAIT

  • The myeloid type I interferon response to myocardial infarction begins in bone marrow and is regulated by Nrf2-activated macrophages
    Sci. Immunol (IF 13.44) Pub Date : 2020-09-25
    David M. Calcagno, Richard P. Ng, Avinash Toomu, Claire Zhang, Kenneth Huang, Aaron D. Aguirre, Ralph Weissleder, Lori B. Daniels, Zhenxing Fu, Kevin R. King

    Sterile tissue injury is thought to locally activate innate immune responses via damage-associated molecular patterns (DAMPs). Whether innate immune pathways are remotely activated remains relatively unexplored. Here, by analyzing ~145,000 single-cell transcriptomes at steady state and after myocardial infarction (MI) in mice and humans, we show that the type I interferon (IFN) response, characterized

  • IL-21 from high-affinity CD4 T cells drives differentiation of brain-resident CD8 T cells during persistent viral infection.
    Sci. Immunol (IF 13.44) Pub Date : 2020-09-18
    Heather M Ren,Elizabeth M Kolawole,Mingqiang Ren,Ge Jin,Colleen S Netherby-Winslow,Quinn Wade,Shwetank,Ziaur S M Rahman,Brian D Evavold,Aron E Lukacher

    Development of tissue-resident memory (TRM) CD8 T cells depends on CD4 T cells. In polyomavirus central nervous system infection, brain CXCR5hi PD-1hi CD4 T cells produce interleukin-21 (IL-21), and CD8 T cells lacking IL-21 receptors (IL21R−/−) fail to become bTRM. IL-21+ CD4 T cells exhibit elevated T cell receptor (TCR) affinity and higher TCR density. IL21R−/− brain CD8 T cells do not express CD103

  • Transcriptomic and clonal characterization of T cells in the human central nervous system.
    Sci. Immunol (IF 13.44) Pub Date : 2020-09-18
    Jenna L Pappalardo,Le Zhang,Maggie K Pecsok,Kelly Perlman,Chrysoula Zografou,Khadir Raddassi,Ahmad Abulaban,Smita Krishnaswamy,Jack Antel,David van Dijk,David A Hafler

    T cells provide critical immune surveillance to the central nervous system (CNS), and the cerebrospinal fluid (CSF) is thought to be a main route for their entry. Further characterization of the state of T cells in the CSF in healthy individuals is important for understanding how T cells provide protective immune surveillance without damaging the delicate environment of the CNS and providing tissue-specific

  • Longitudinal immune profiling reveals key myeloid signatures associated with COVID-19.
    Sci. Immunol (IF 13.44) Pub Date : 2020-09-17
    Elizabeth R Mann,Madhvi Menon,Sean Blandin Knight,Joanne E Konkel,Christopher Jagger,Tovah N Shaw,Siddharth Krishnan,Magnus Rattray,Andrew Ustianowski,Nawar Diar Bakerly,Paul Dark,Graham Lord,Angela Simpson,Timothy Felton,Ling-Pei Ho,,Marc Feldmann,,John R Grainger,Tracy Hussell

    COVID-19 pathogenesis is associated with an exaggerated immune response. However, the specific cellular mediators and inflammatory components driving diverse clinical disease outcomes remain poorly understood. We undertook longitudinal immune profiling on both whole blood and peripheral blood mononuclear cells (PBMCs) of hospitalized patients during the peak of the COVID-19 pandemic in the UK. Here

  • 更新日期:2020-09-18
  • Type I interferon signaling in fibroblastic reticular cells prevents exhaustive activation of antiviral CD8+ T cells.
    Sci. Immunol (IF 13.44) Pub Date : 2020-09-11
    Christian Perez-Shibayama,Ulrika Islander,Mechthild Lütge,Hung-Wei Cheng,Lucas Onder,Sandra S Ring,Angelina De Martin,Mario Novkovic,Julia Colston,Cristina Gil-Cruz,Burkhard Ludewig

    Fibroblastic reticular cells (FRCs) are stromal cells that actively promote the induction of immune responses by coordinating the interaction of innate and adaptive immune cells. However, whether and to which extent immune cell activation is determined by lymph node FRC reprogramming during acute viral infection has remained unexplored. Here, we genetically ablated expression of the type I interferon-α

  • Sympathetic nervous tone limits the development of myeloid-derived suppressor cells.
    Sci. Immunol (IF 13.44) Pub Date : 2020-09-11
    James T Nevin,Marmar Moussa,William L Corwin,Ion I Mandoiu,Pramod K Srivastava

    Sympathetic nerves that innervate lymphoid organs regulate immune development and function by releasing norepinephrine that is sensed by immune cells via their expression of adrenergic receptors. Here, we demonstrate that ablation of sympathetic nervous system (SNS) signaling suppresses tumor immunity, and we dissect the mechanism of such immune suppression. We report that disruption of the SNS in

  • The transcription factor E2A activates multiple enhancers that drive Rag expression in developing T and B cells.
    Sci. Immunol (IF 13.44) Pub Date : 2020-09-04
    Kazuko Miyazaki,Hitomi Watanabe,Genki Yoshikawa,Kenian Chen,Reiko Hidaka,Yuki Aitani,Kai Osawa,Rie Takeda,Yotaro Ochi,Shizue Tani-Ichi,Takuya Uehata,Osamu Takeuchi,Koichi Ikuta,Seishi Ogawa,Gen Kondoh,Yin C Lin,Hiroyuki Ogata,Masaki Miyazaki

    Cell type–specific gene expression is driven by the interplay between lineage-specific transcription factors and cis-regulatory elements to which they bind. Adaptive immunity relies on RAG-mediated assembly of T cell receptor (TCR) and immunoglobulin (Ig) genes. Although Rag1 and Rag2 expression is largely restricted to adaptive lymphoid lineage cells, it remains unclear how Rag gene expression is

  • Immune surveillance of the liver by T cells.
    Sci. Immunol (IF 13.44) Pub Date : 2020-09-04
    Xenia Ficht,Matteo Iannacone

    The liver is the target of several infectious, inflammatory, and neoplastic diseases, which affect hundreds of millions of people worldwide and cause an estimated death toll of more than 2 million people each year. Dysregulation of T cell responses has been implicated in the pathogenesis of these diseases; hence, it is critically important to understand the function and fate of T cells in the liver

  • Keepin' it regulatory: Foxp3 gets a BAFfling SWItch.
    Sci. Immunol (IF 13.44) Pub Date : 2020-09-04
    Maxime J Kinet,Michael D Rosenblum

    A novel role for SWI/SNF complexes in tuning Foxp3 expression and activity in Tregs.

  • Illuminating the core of adaptive immunity-how the regulatory genome controls Rag chromatin dynamics.
    Sci. Immunol (IF 13.44) Pub Date : 2020-09-04
    Xun Wang,Ellen V Rothenberg

    E2A specifies adaptive immunity by instructing large-scale topological changes for Rag gene super-enhancer formation (see the related Research Article by Miyazaki et al.).

  • Activation of TRPA1 nociceptor promotes systemic adult mammalian skin regeneration.
    Sci. Immunol (IF 13.44) Pub Date : 2020-08-28
    Jenny J Wei,Hali S Kim,Casey A Spencer,Donna Brennan-Crispi,Ying Zheng,Nicolette M Johnson,Misha Rosenbach,Christopher Miller,Denis H Leung,George Cotsarelis,Thomas H Leung

    Adult mammalian wounds, with rare exception, heal with fibrotic scars that severely disrupt tissue architecture and function. Regenerative medicine seeks methods to avoid scar formation and restore the original tissue structures. We show in three adult mouse models that pharmacologic activation of the nociceptor TRPA1 on cutaneous sensory neurons reduces scar formation and can also promote tissue regeneration

  • Heterogeneity and clonal relationships of adaptive immune cells in ulcerative colitis revealed by single-cell analyses.
    Sci. Immunol (IF 13.44) Pub Date : 2020-08-21
    Brigid S Boland,Zhaoren He,Matthew S Tsai,Jocelyn G Olvera,Kyla D Omilusik,Han G Duong,Eleanor S Kim,Abigail E Limary,Wenhao Jin,J Justin Milner,Bingfei Yu,Shefali A Patel,Tiani L Louis,Tiffani Tysl,Nadia S Kurd,Alexandra Bortnick,Lauren K Quezada,Jad N Kanbar,Ara Miralles,Danny Huylebroeck,Mark A Valasek,Parambir S Dulai,Siddharth Singh,Li-Fan Lu,Jack D Bui,Cornelis Murre,William J Sandborn,Ananda

    Inflammatory bowel disease (IBD) encompasses a spectrum of gastrointestinal disorders driven by dysregulated immune responses against gut microbiota. We integrated single-cell RNA and antigen receptor sequencing to elucidate key components, cellular states, and clonal relationships of the peripheral and gastrointestinal mucosal immune systems in health and ulcerative colitis (UC). UC was associated

  • Targeting Piezo1 unleashes innate immunity against cancer and infectious disease.
    Sci. Immunol (IF 13.44) Pub Date : 2020-08-21
    Berk Aykut,Ruonan Chen,Jacqueline I Kim,Dongling Wu,Sorin A A Shadaloey,Raquel Abengozar,Pamela Preiss,Anjana Saxena,Smruti Pushalkar,Joshua Leinwand,Brian Diskin,Wei Wang,Gregor Werba,Matthew Berman,Steve Ki Buom Lee,Alireza Khodadadi-Jamayran,Deepak Saxena,William A Coetzee,George Miller

    Piezo1 is a mechanosensitive ion channel that has gained recognition for its role in regulating diverse physiological processes. However, the influence of Piezo1 in inflammatory disease, including infection and tumor immunity, is not well studied. We postulated that Piezo1 links physical forces to immune regulation in myeloid cells. We found signal transduction via Piezo1 in myeloid cells and established

  • Natural killer cell immunotypes related to COVID-19 disease severity.
    Sci. Immunol (IF 13.44) Pub Date : 2020-08-21
    Christopher Maucourant,Iva Filipovic,Andrea Ponzetta,Soo Aleman,Martin Cornillet,Laura Hertwig,Benedikt Strunz,Antonio Lentini,Björn Reinius,Demi Brownlie,Angelica Cuapio,Eivind Heggernes Ask,Ryan M Hull,Alvaro Haroun-Izquierdo,Marie Schaffer,Jonas Klingström,Elin Folkesson,Marcus Buggert,Johan K Sandberg,Lars I Eriksson,Olav Rooyackers,Hans-Gustaf Ljunggren,Karl-Johan Malmberg,Jakob Michaëlsson,Nicole

    Understanding innate immune responses in COVID-19 is important to decipher mechanisms of host responses and interpret disease pathogenesis. Natural killer (NK) cells are innate effector lymphocytes that respond to acute viral infections but might also contribute to immunopathology. Using 28-color flow cytometry, we here reveal strong NK cell activation across distinct subsets in peripheral blood of

  • HVEM signaling promotes protective antibody-dependent cellular cytotoxicity (ADCC) vaccine responses to herpes simplex viruses.
    Sci. Immunol (IF 13.44) Pub Date : 2020-08-14
    Clare Burn Aschner,Lip Nam Loh,Benjamin Galen,Isabel Delwel,Rohit K Jangra,Scott J Garforth,Kartik Chandran,Steven Almo,William R Jacobs,Carl F Ware,Betsy C Herold

    Herpes simplex virus (HSV) glycoprotein D (gD) not only is required for virus entry and cell-to-cell spread but also binds the host immunomodulatory molecule, HVEM, blocking interactions with its ligands. Natural infection primarily elicits neutralizing antibodies targeting gD, but subunit protein vaccines designed to induce this response have failed clinically. In contrast, preclinical studies demonstrate

  • An IL-2 mutein engineered to promote expansion of regulatory T cells arrests ongoing autoimmunity in mice.
    Sci. Immunol (IF 13.44) Pub Date : 2020-08-14
    Liliane Khoryati,Minh Nguyet Pham,McKenna Sherve,Swarnima Kumari,Kevin Cook,Josh Pearson,Marika Bogdani,Daniel J Campbell,Marc A Gavin

    Interleukin-2 (IL-2) controls the homeostasis and function of regulatory T (Treg) cells, and defects in the IL-2 pathway contribute to multiple autoimmune diseases. Although recombinant IL-2 therapy has been efficacious in certain inflammatory conditions, the capacity for IL-2 to also activate inflammatory effector responses highlights the need for IL-2–based therapeutics with improved Treg cell specificity

  • The (inner) world according to GARP: Genetic susceptibility and regulatory T cells.
    Sci. Immunol (IF 13.44) Pub Date : 2020-08-07
    Shiv Pillai

    A human autoimmune and allergic disease susceptibility variant on chromosome 11 results in the reduced expression of the gene encoding the GARP protein and thus compromises the function of regulatory T cells.

  • Resident TH17 cells "break bad" in kidney autoimmunity.
    Sci. Immunol (IF 13.44) Pub Date : 2020-08-07
    Marcus Buggert

    Resident memory TH17 cells (TRM17 cells) are induced by microbial infections in kidneys and amplify renal autoimmunity.

  • Pathogen-induced tissue-resident memory TH17 (TRM17) cells amplify autoimmune kidney disease.
    Sci. Immunol (IF 13.44) Pub Date : 2020-08-07
    Christian F Krebs,Daniel Reimers,Yu Zhao,Hans-Joachim Paust,Patricia Bartsch,Sarah Nuñez,Mariana V Rosemblatt,Malte Hellmig,Christoph Kilian,Alina Borchers,Leon U B Enk,Michael Zinke,Martina Becker,Joanna Schmid,Stefanie Klinge,Milagros N Wong,Victor G Puelles,Constantin Schmidt,Tabea Bertram,Natascha Stumpf,Elion Hoxha,Catherine Meyer-Schwesinger,Maja T Lindenmeyer,Clemens D Cohen,Michael Rink,Christian

    Although it is well established that microbial infections predispose to autoimmune diseases, the underlying mechanisms remain poorly understood. After infection, tissue-resident memory T (TRM) cells persist in peripheral organs and provide immune protection against reinfection. However, whether TRM cells participate in responses unrelated to the primary infection, such as autoimmune inflammation, is

  • Functional heterogeneity of alveolar macrophage population based on expression of CXCL2.
    Sci. Immunol (IF 13.44) Pub Date : 2020-08-07
    Shengjie Xu-Vanpala,M Elizabeth Deerhake,Joshua D Wheaton,Morgan E Parker,Praveen R Juvvadi,Nancie MacIver,Maria Ciofani,Mari L Shinohara

    Alveolar macrophages (AMs) are the major lung-resident macrophages and have contradictory functions. AMs maintain tolerance and tissue homeostasis, but they also initiate strong inflammatory responses. However, such opposing roles within the AM population were not known to be simultaneously generated and coexist. Here, we uncovered heterogeneous AM subpopulations generated in response to two distinct

  • Gut T cell-independent IgA responses to commensal bacteria require engagement of the TACI receptor on B cells.
    Sci. Immunol (IF 13.44) Pub Date : 2020-07-31
    E K Grasset,A Chorny,S Casas-Recasens,C Gutzeit,G Bongers,I Thomsen,L Chen,Z He,D B Matthews,M A Oropallo,P Veeramreddy,M Uzzan,A Mortha,J Carrillo,B S Reis,M Ramanujam,J Sintes,G Magri,P J Maglione,C Cunningham-Rundles,R J Bram,J Faith,S Mehandru,O Pabst,A Cerutti

    The gut mounts secretory immunoglobulin A (SIgA) responses to commensal bacteria through nonredundant T cell–dependent (TD) and T cell–independent (TI) pathways that promote the establishment of mutualistic host-microbiota interactions. SIgAs from the TD pathway target penetrant bacteria, and their induction requires engagement of CD40 on B cells by CD40 ligand on T follicular helper cells. In contrast

  • SARS-CoV-2 seroprevalence among parturient women in Philadelphia.
    Sci. Immunol (IF 13.44) Pub Date : 2020-07-29
    Dustin D Flannery,Sigrid Gouma,Miren B Dhudasia,Sagori Mukhopadhyay,Madeline R Pfeifer,Emily C Woodford,Jeffrey S Gerber,Claudia P Arevalo,Marcus J Bolton,Madison E Weirick,Eileen C Goodwin,Elizabeth M Anderson,Allison R Greenplate,Justin Kim,Nicholas Han,Ajinkya Pattekar,Jeanette Dougherty,Oliva Kuthuru,Divij Mathew,Amy E Baxter,Laura A Vella,JoEllen Weaver,Anurag Verma,Rita Leite,Jeffrey S Morris

    Limited data are available for pregnant women affected by SARS-CoV-2. Serological tests are critically important for determining SARS-CoV-2 exposures within both individuals and populations. We validated a SARS-CoV-2 spike receptor binding domain serological test using 834 pre-pandemic samples and 31 samples from COVID-19 recovered donors. We then completed SARS-CoV-2 serological testing of 1,293 parturient

  • Absence of mucosal-associated invariant T cells in a person with a homozygous point mutation in MR1.
    Sci. Immunol (IF 13.44) Pub Date : 2020-07-24
    Lauren J Howson,Wael Awad,Anouk von Borstel,Hui Jing Lim,Hamish E G McWilliam,Maria L Sandoval-Romero,Shamik Majumdar,Abdul Rezzak Hamzeh,Thomas D Andrews,David H McDermott,Philip M Murphy,Jérôme Le Nours,Jeffrey Y W Mak,Ligong Liu,David P Fairlie,James McCluskey,Jose A Villadangos,Matthew C Cook,Stephen J Turner,Martin S Davey,Samar Ojaimi,Jamie Rossjohn

    The role unconventional T cells play in protective immunity in humans is unclear. Mucosal-associated invariant T (MAIT) cells are an unconventional T cell subset restricted to the antigen-presenting molecule MR1. Here, we report the discovery of a patient homozygous for a rare Arg31His (R9H in the mature protein) mutation in MR1 who has a history of difficult-to-treat viral and bacterial infections

  • Shed it, and help-LAG3 cleavage drives conventional CD4+ T cells to overcome resistance to PD-1 immunotherapy.
    Sci. Immunol (IF 13.44) Pub Date : 2020-07-17
    Lea Seidel,Bertram Bengsch

    LAG3 cleavage from conventional CD4+ T cells, but not CD8+ T cells, is required for effective PD-1 blockade.

  • SARS-CoV-2 T cell immunity: Specificity, function, durability, and role in protection.
    Sci. Immunol (IF 13.44) Pub Date : 2020-07-17
    Daniel M Altmann,Rosemary J Boyton

    In efforts to synthesize a clear understanding of SARS-CoV-2 protective immunity, antibody analysis has been paralleled by T cell studies across asymptomatic, mild and severe COVID-19. Defining CD4 and CD8 effector functions in protection is important considering that antibody responses appear short-lived and T cell memory is potentially more durable. To fully understand population level immunity,

  • Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding.
    Sci. Immunol (IF 13.44) Pub Date : 2020-07-17
    Lawrence P Andrews,Ashwin Somasundaram,Jessica M Moskovitz,Andrea L Szymczak-Workman,Chang Liu,Anthony R Cillo,Huang Lin,Daniel P Normolle,Kelly D Moynihan,Ichiro Taniuchi,Darrell J Irvine,John M Kirkwood,Evan J Lipson,Robert L Ferris,Tullia C Bruno,Creg J Workman,Dario A A Vignali

    Mechanisms of resistance to cancer immunotherapy remain poorly understood. Lymphocyte activation gene–3 (LAG3) signaling is regulated by a disintegrin and metalloprotease domain-containing protein–10 (ADAM10)– and ADAM17-mediated cell surface shedding. Here, we show that mice expressing a metalloprotease-resistant, noncleavable LAG3 mutant (LAG3NC) are resistant to PD1 blockade and fail to mount an

  • TH17 cells require ongoing classic IL-6 receptor signaling to retain transcriptional and functional identity.
    Sci. Immunol (IF 13.44) Pub Date : 2020-07-17
    Stacey N Harbour,Daniel F DiToro,Steven J Witte,Carlene L Zindl,Min Gao,Trenton R Schoeb,Gareth W Jones,Simon A Jones,Robin D Hatton,Casey T Weaver

    Acting in concert with TGF-β, interleukin-6 (IL-6) signaling induces T helper 17 (TH17) cell development by programming TH17-related genes via signal transducers and activators of transcription 3 (STAT3). A role for IL-6 signaling beyond the inductive phase of TH17 cell development has not been defined because IL-23 signaling downstream of TH17 cell induction also activates STAT3 and is thought responsible

  • Comprehensive mapping of immune perturbations associated with severe COVID-19.
    Sci. Immunol (IF 13.44) Pub Date : 2020-07-15
    Leticia Kuri-Cervantes,M Betina Pampena,Wenzhao Meng,Aaron M Rosenfeld,Caroline A G Ittner,Ariel R Weisman,Roseline S Agyekum,Divij Mathew,Amy E Baxter,Laura A Vella,Oliva Kuthuru,Sokratis A Apostolidis,Luanne Bershaw,Jeanette Dougherty,Allison R Greenplate,Ajinkya Pattekar,Justin Kim,Nicholas Han,Sigrid Gouma,Madison E Weirick,Claudia P Arevalo,Marcus J Bolton,Eileen C Goodwin,Elizabeth M Anderson

    Although critical illness has been associated with SARS-CoV-2-induced hyperinflammation, the immune correlates of severe COVID-19 remain unclear. Here, we comprehensively analyzed peripheral blood immune perturbations in 42 SARS-CoV-2 infected and recovered individuals. We identified extensive induction and activation of multiple immune lineages, including T cell activation, oligoclonal plasmablast

  • Human inborn errors of immunity: An expanding universe.
    Sci. Immunol (IF 13.44) Pub Date : 2020-07-10
    Luigi D Notarangelo,Rosa Bacchetta,Jean-Laurent Casanova,Helen C Su

    Molecular, cellular, and clinical studies of human inborn errors of immunity have revolutionized our understanding of their pathogenesis, considerably broadened their spectrum of immunological and clinical phenotypes, and enabled successful targeted therapeutic interventions. These studies have also been of great scientific merit, challenging a number of immunological notions initially established

  • Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19.
    Sci. Immunol (IF 13.44) Pub Date : 2020-07-10
    Jeong Seok Lee,Seongwan Park,Hye Won Jeong,Jin Young Ahn,Seong Jin Choi,Hoyoung Lee,Baekgyu Choi,Su Kyung Nam,Moa Sa,Ji-Soo Kwon,Su Jin Jeong,Heung Kyu Lee,Sung Ho Park,Su-Hyung Park,Jun Yong Choi,Sung-Han Kim,Inkyung Jung,Eui-Cheol Shin

    Although most SARS-CoV-2-infected individuals experience mild coronavirus disease 2019 (COVID-19), some patients suffer from severe COVID-19, which is accompanied by acute respiratory distress syndrome and systemic inflammation. To identify factors driving severe progression of COVID-19, we performed single-cell RNA-seq using peripheral blood mononuclear cells (PBMCs) obtained from healthy donors,

  • The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity.
    Sci. Immunol (IF 13.44) Pub Date : 2020-07-10
    Elisabeth Salzer,Samaneh Zoghi,Máté G Kiss,Frieda Kage,Christina Rashkova,Stephanie Stahnke,Matthias Haimel,René Platzer,Michael Caldera,Rico Chandra Ardy,Birgit Hoeger,Jana Block,David Medgyesi,Celine Sin,Sepideh Shahkarami,Renate Kain,Vahid Ziaee,Peter Hammerl,Christoph Bock,Jörg Menche,Loïc Dupré,Johannes B Huppa,Michael Sixt,Alexis Lomakin,Klemens Rottner,Christoph J Binder,Theresia E B Stradal

    The WAVE regulatory complex (WRC) is crucial for assembly of the peripheral branched actin network constituting one of the main drivers of eukaryotic cell migration. Here, we uncover an essential role of the hematopoietic-specific WRC component HEM1 for immune cell development. Germline-encoded HEM1 deficiency underlies an inborn error of immunity with systemic autoimmunity, at cellular level marked

  • Human effector T cells express TOX-Not so "TOX"ic after all.
    Sci. Immunol (IF 13.44) Pub Date : 2020-07-03
    Daniel T Utzschneider,Axel Kallies

    TOX expression is not restricted to exhausted T cells but a characteristic of all human effector CD8+ T cells.

  • TOX is expressed by exhausted and polyfunctional human effector memory CD8+ T cells.
    Sci. Immunol (IF 13.44) Pub Date : 2020-07-03
    Takuya Sekine,André Perez-Potti,Son Nguyen,Jean-Baptiste Gorin,Vincent H Wu,Emma Gostick,Sian Llewellyn-Lacey,Quirin Hammer,Sara Falck-Jones,Sindhu Vangeti,Meng Yu,Anna Smed-Sörensen,Ahmed Gaballa,Michael Uhlin,Johan K Sandberg,Christian Brander,Piotr Nowak,Paul A Goepfert,David A Price,Michael R Betts,Marcus Buggert

    CD8+ T cell exhaustion is a hallmark of many cancers and chronic infections. In mice, T cell factor 1 (TCF-1) maintains exhausted CD8+ T cell responses, whereas thymocyte selection-associated HMG box (TOX) is required for the epigenetic remodeling and survival of exhausted CD8+ T cells. However, it has remained unclear to what extent these transcription factors play analogous roles in humans. In this

  • Human antibodies neutralize enterovirus D68 and protect against infection and paralytic disease.
    Sci. Immunol (IF 13.44) Pub Date : 2020-07-03
    Matthew R Vogt,Jianing Fu,Nurgun Kose,Lauren E Williamson,Robin Bombardi,Ian Setliff,Ivelin S Georgiev,Thomas Klose,Michael G Rossmann,Yury A Bochkov,James E Gern,Richard J Kuhn,James E Crowe

    Enterovirus D68 (EV-D68) causes outbreaks of respiratory illness, and there is increasing evidence that it causes outbreaks of acute flaccid myelitis (AFM). There are no licensed therapies to prevent or treat EV-D68 infection or AFM disease. We isolated a panel of EV-D68–reactive human monoclonal antibodies that recognize diverse antigenic variants from participants with prior infection. One potently

  • Let's talk about sex.
    Sci. Immunol (IF 13.44) Pub Date : 2020-07-03
    James C Patti,Gabriel K Griffin

    Complement gene variation drives sex biases in autoimmune disease.

  • Finding Camel-ot: A Holy Grail against pandemic SARS-CoV-2?
    Sci. Immunol (IF 13.44) Pub Date : 2020-07-03
    Deborah Soong,Rachel Leeman,Asha Pillai

    Engineered camelid antibody multimers can potently block SARS-CoV-2 viral entry.

  • Glycolipid-peptide vaccination induces liver-resident memory CD8+ T cells that protect against rodent malaria.
    Sci. Immunol (IF 13.44) Pub Date : 2020-06-26
    Lauren E Holz,Yu Cheng Chua,Maria N de Menezes,Regan J Anderson,Sarah L Draper,Benjamin J Compton,Susanna T S Chan,Juby Mathew,Jasmine Li,Lukasz Kedzierski,Zhongfang Wang,Lynette Beattie,Matthias H Enders,Sonia Ghilas,Rose May,Thiago M Steiner,Joshua Lange,Daniel Fernandez-Ruiz,Ana Maria Valencia-Hernandez,Taryn L Osmond,Kathryn J Farrand,Rebecca Seneviratna,Catarina F Almeida,Kirsteen M Tullett,Patrick

    Liver resident-memory CD8+ T cells (TRM cells) can kill liver-stage Plasmodium-infected cells and prevent malaria, but simple vaccines for generating this important immune population are lacking. Here, we report the development of a fully synthetic self-adjuvanting glycolipid-peptide conjugate vaccine designed to efficiently induce liver TRM cells. Upon cleavage in vivo, the glycolipid-peptide conjugate

  • Phenotype and kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory distress syndrome.
    Sci. Immunol (IF 13.44) Pub Date : 2020-06-26
    Daniela Weiskopf,Katharina S Schmitz,Matthijs P Raadsen,Alba Grifoni,Nisreen M A Okba,Henrik Endeman,Johannes P C van den Akker,Richard Molenkamp,Marion P G Koopmans,Eric C M van Gorp,Bart L Haagmans,Rik L de Swart,Alessandro Sette,Rory D de Vries

    SARS-CoV-2 has been identified as the causative agent of a global outbreak of respiratory tract disease (COVID-19). In some patients the infection results in moderate to severe acute respiratory distress syndrome (ARDS), requiring invasive mechanical ventilation. High serum levels of IL-6, IL-10 and an immune hyperresponsiveness referred to as a ‘cytokine storm’ have been associated with poor clinical

  • Rate of replenishment and microenvironment contribute to the sexually dimorphic phenotype and function of peritoneal macrophages.
    Sci. Immunol (IF 13.44) Pub Date : 2020-06-19
    C C Bain,D A Gibson,N J Steers,K Boufea,P A Louwe,C Doherty,V González-Huici,R Gentek,M Magalhaes-Pinto,T Shaw,M Bajénoff,C Bénézech,S R Walmsley,D H Dockrell,P T K Saunders,N N Batada,S J Jenkins

    Macrophages reside in the body cavities where they maintain serosal homeostasis and provide immune surveillance. Peritoneal macrophages are implicated in the etiology of pathologies including peritonitis, endometriosis, and metastatic cancer; thus, understanding the factors that govern their behavior is vital. Using a combination of fate mapping techniques, we have investigated the impact of sex and

  • 3M-052, a synthetic TLR-7/8 agonist, induces durable HIV-1 envelope-specific plasma cells and humoral immunity in nonhuman primates.
    Sci. Immunol (IF 13.44) Pub Date : 2020-06-19
    Sudhir Pai Kasturi,Mohammed Ata Ur Rasheed,Colin Havenar-Daughton,Mathew Pham,Traci Legere,Zarpheen Jinnah Sher,Yevgeny Kovalenkov,Sanjeev Gumber,Jessica Y Huang,Raphael Gottardo,William Fulp,Alicia Sato,Sheetal Sawant,Sherry Stanfield-Oakley,Nicole Yates,Celia LaBranche,S Munir Alam,Georgia Tomaras,Guido Ferrari,David Montefiori,Jens Wrammert,Francois Villinger,Mark Tomai,John Vasilakos,Christopher

    A fundamental challenge in vaccinology is learning how to induce durable antibody responses. Live viral vaccines induce antibody responses that last a lifetime, but those induced with subunit vaccines wane rapidly. Studies in mice and humans have established that long-lived plasma cells (LLPCs) in the bone marrow (BM) are critical mediators of durable antibody responses. Here, we present data that

  • Ahr-Foxp3-RORγt axis controls gut homing of CD4+ T cells by regulating GPR15.
    Sci. Immunol (IF 13.44) Pub Date : 2020-06-12
    Lifeng Xiong,Joseph W Dean,Zheng Fu,Kristen N Oliff,John W Bostick,Jian Ye,Zongming E Chen,Marcus Mühlbauer,Liang Zhou

    The orphan chemoattractant receptor GPR15 is important for homing T lymphocytes to the large intestine, thereby maintaining intestinal immune homeostasis. However, the molecular mechanisms underlying the regulation of GPR15 expression remain elusive. Here, we show a central role of the aryl hydrocarbon receptor (Ahr) in promoting GPR15 expression in both mice and human, thus gut homing of T lymphocytes

  • Single-cell transcriptomic analysis of allergen-specific T cells in allergy and asthma.
    Sci. Immunol (IF 13.44) Pub Date : 2020-06-12
    Grégory Seumois,Ciro Ramírez-Suástegui,Benjamin J Schmiedel,Shu Liang,Bjoern Peters,Alessandro Sette,Pandurangan Vijayanand

    CD4+ T helper (TH) cells and regulatory T (Treg) cells that respond to common allergens play an important role in driving and dampening airway inflammation in patients with asthma. Until recently, direct, unbiased molecular analysis of allergen-reactive TH and Treg cells has not been possible. To better understand the diversity of these T cell subsets in allergy and asthma, we analyzed the single-cell

  • A singular role for interleukin-9 in the development of asthma.
    Sci. Immunol (IF 13.44) Pub Date : 2020-06-12
    Jonathan M Coquet

    Interleukin-9 expression by T helper cells marks allergic individuals who develop asthma (see the related Research Article by Seumois et al.).

  • The receptor binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients.
    Sci. Immunol (IF 13.44) Pub Date : 2020-06-11
    Lakshmanane Premkumar,Bruno Segovia-Chumbez,Ramesh Jadi,David R Martinez,Rajendra Raut,Alena Markmann,Caleb Cornaby,Luther Bartelt,Susan Weiss,Yara Park,Caitlin E Edwards,Eric Weimer,Erin M Scherer,Nadine Rouphael,Srilatha Edupuganti,Daniela Weiskopf,Longping V Tse,Yixuan J Hou,David Margolis,Alessandro Sette,Matthew H Collins,John Schmitz,Ralph S Baric,Aravinda M de Silva

    The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that first emerged in late 2019 is responsible for a pandemic of severe respiratory illness. People infected with this highly contagious virus can present with clinically inapparent, mild, or severe disease. Currently, the virus infection in individuals and at the population level is being monitored by PCR testing of symptomatic patients

  • T cell engagement of cross-presenting microglia protects the brain from a nasal virus infection.
    Sci. Immunol (IF 13.44) Pub Date : 2020-06-05
    E Ashley Moseman,Alexa C Blanchard,Debasis Nayak,Dorian B McGavern

    The neuroepithelium is a nasal barrier surface populated by olfactory sensory neurons that detect odorants in the airway and convey this information directly to the brain via axon fibers. This barrier surface is especially vulnerable to infection, yet respiratory infections rarely cause fatal encephalitis, suggesting a highly evolved immunological defense. Here, using a mouse model, we sought to understand

  • Oral epithelial IL-22/STAT3 signaling licenses IL-17-mediated immunity to oral mucosal candidiasis.
    Sci. Immunol (IF 13.44) Pub Date : 2020-06-05
    Felix E Y Aggor,Timothy J Break,Giraldina Trevejo-Nuñez,Natasha Whibley,Bianca M Coleman,Rachel D Bailey,Daniel H Kaplan,Julian R Naglik,Wei Shan,Amol C Shetty,Carrie McCracken,Scott K Durum,Partha S Biswas,Vincent M Bruno,Jay K Kolls,Michail S Lionakis,Sarah L Gaffen

    Oropharyngeal candidiasis (OPC; thrush) is an opportunistic infection caused by the commensal fungus Candida albicans. Interleukin-17 (IL-17) and IL-22 are cytokines produced by type 17 lymphocytes. Both cytokines mediate antifungal immunity yet activate quite distinct downstream signaling pathways. While much is now understood about how IL-17 promotes immunity in OPC, the activities of IL-22 are far

  • Sweet and low-autoantibodies deny oligodendrocytes their sugar fix.
    Sci. Immunol (IF 13.44) Pub Date : 2020-06-05
    Amanda L Hernandez,Kevin C O'Connor

    Pathogenic autoantibodies causing encephalopathy modify the expression of the glucose transporter in oligodendrocytes.

  • B cells: Your besT-bet against the flu.
    Sci. Immunol (IF 13.44) Pub Date : 2020-06-05
    Kenneth Zhou,Stephanie Eisenbarth

    T-bet+ memory B cells are a distinct subset that home to the spleen and produce neutralizing antibodies against influenza.

  • Inhibition of Bruton tyrosine kinase in patients with severe COVID-19.
    Sci. Immunol (IF 13.44) Pub Date : 2020-06-05
    Mark Roschewski,Michail S Lionakis,Jeff P Sharman,Joseph Roswarski,Andre Goy,M Andrew Monticelli,Michael Roshon,Stephen H Wrzesinski,Jigar V Desai,Marissa A Zarakas,Jacob Collen,Keith Rose,Ahmed Hamdy,Raquel Izumi,George W Wright,Kevin K Chung,Jose Baselga,Louis M Staudt,Wyndham H Wilson

    Patients with severe COVID-19 have a hyperinflammatory immune response suggestive of macrophage activation. Bruton tyrosine kinase (BTK) regulates macrophage signaling and activation. Acalabrutinib, a selective BTK inhibitor, was administered off-label to 19 patients hospitalized with severe COVID-19 (11 on supplemental oxygen; 8 on mechanical ventilation), 18 of whom had increasing oxygen requirements

  • IRF5 guides monocytes toward an inflammatory CD11c+ macrophage phenotype and promotes intestinal inflammation.
    Sci. Immunol (IF 13.44) Pub Date : 2020-05-22
    Alastair L Corbin,Maria Gomez-Vazquez,Dorothée L Berthold,Moustafa Attar,Isabelle C Arnold,Fiona M Powrie,Stephen N Sansom,Irina A Udalova

    Mononuclear phagocytes (MNPs) are vital for maintaining intestinal homeostasis but, in response to acute microbial stimulation, can also trigger immunopathology, accelerating recruitment of Ly6Chi monocytes to the gut. The regulators that control monocyte tissue adaptation in the gut remain poorly understood. Interferon regulatory factor 5 (IRF5) is a transcription factor previously shown to play a

  • Serology for SARS-CoV-2: Apprehensions, opportunities, and the path forward.
    Sci. Immunol (IF 13.44) Pub Date : 2020-05-19
    Juliet E Bryant,Andrew S Azman,Matthew J Ferrari,Benjamin F Arnold,Maciej F Boni,Yap Boum,Kyla Hayford,Francisco J Luquero,Michael J Mina,Isabel Rodriguez-Barraquer,Joseph T Wu,Djibril Wade,Guy Vernet,Daniel T Leung

    Serological testing for SARS-CoV-2 has enormous potential to contribute to COVID-19 pandemic response efforts. However, the required performance characteristics of antibody tests will critically depend on the use case (individual-level vs. population-level).

  • Early precursors and molecular determinants of tissue-resident memory CD8+ T lymphocytes revealed by single-cell RNA sequencing.
    Sci. Immunol (IF 13.44) Pub Date : 2020-05-15
    Nadia S Kurd,Zhaoren He,Tiani L Louis,J Justin Milner,Kyla D Omilusik,Wenhao Jin,Matthew S Tsai,Christella E Widjaja,Jad N Kanbar,Jocelyn G Olvera,Tiffani Tysl,Lauren K Quezada,Brigid S Boland,Wendy J Huang,Cornelis Murre,Ananda W Goldrath,Gene W Yeo,John T Chang

    During an immune response to microbial infection, CD8+ T cells give rise to distinct classes of cellular progeny that coordinately mediate clearance of the pathogen and provide long-lasting protection against reinfection, including a subset of noncirculating tissue-resident memory (TRM) cells that mediate potent protection within nonlymphoid tissues. Here, we used single-cell RNA sequencing to examine

  • TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes.
    Sci. Immunol (IF 13.44) Pub Date : 2020-05-13
    Ruochen Zang,Maria Florencia Gomez Castro,Broc T McCune,Qiru Zeng,Paul W Rothlauf,Naomi M Sonnek,Zhuoming Liu,Kevin F Brulois,Xin Wang,Harry B Greenberg,Michael S Diamond,Matthew A Ciorba,Sean P J Whelan,Siyuan Ding

    Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA are frequently observed in COVID-19 patients. However, it is unclear whether SARS-CoV-2 replicates in the human intestine and contributes to possible fecal-oral transmission. Here, we report productive infection of SARS-CoV-2 in ACE2+ mature enterocytes in human small intestinal enteroids. Expression of two mucosa-specific serine proteases

  • Divergent T follicular helper cell requirement for IgA and IgE production to peanut during allergic sensitization.
    Sci. Immunol (IF 13.44) Pub Date : 2020-05-08
    Biyan Zhang,Elise Liu,Jake A Gertie,Julie Joseph,Lan Xu,Elisha Y Pinker,Daniel A Waizman,Jason Catanzaro,Kedir Hussen Hamza,Katharina Lahl,Uthaman Gowthaman,Stephanie C Eisenbarth

    Immunoglobulin A (IgA) is the dominant antibody isotype in the gut and has been shown to regulate microbiota. Mucosal IgA is also widely believed to prevent food allergens from penetrating the gut lining. Even though recent work has elucidated how bacteria-reactive IgA is induced, little is known about how IgA to food antigens is regulated. Although IgA is presumed to be induced in a healthy gut at

  • HiJAKing SARS-CoV-2? The potential role of JAK inhibitors in the management of COVID-19.
    Sci. Immunol (IF 13.44) Pub Date : 2020-05-08
    Francesca Romana Spinelli,Fabrizio Conti,Massimo Gadina

    JAK kinase inhibitors are being investigated as a way of managing cytokine storm in severe COVID-19 patients.

  • Sestrins teach old T cells new tricks.
    Sci. Immunol (IF 13.44) Pub Date : 2020-05-01
    Jonathan S Maltzman

    Sestrin proteins dampen TCR signaling and induce antigen-independent natural killer-like cytotoxicity in highly differentiated CD8 T cells.

  • A respiratory syncytial virus (RSV) F protein nanoparticle vaccine focuses antibody responses to a conserved neutralization domain.
    Sci. Immunol (IF 13.44) Pub Date : 2020-05-01
    Kurt A Swanson,Jennifer N Rainho-Tomko,Zachary P Williams,Lilibeth Lanza,Michael Peredelchuk,Michael Kishko,Vincent Pavot,Judith Alamares-Sapuay,Haritha Adhikarla,Sankalp Gupta,Sudha Chivukula,Scott Gallichan,Linong Zhang,Nicholas Jackson,Heesik Yoon,Darin Edwards,Chih-Jen Wei,Gary J Nabel

    A stabilized form of the respiratory syncytial virus (RSV) fusion (F) protein has been explored as a vaccine to prevent viral infection because it presents several potent neutralizing epitopes. Here, we used a structure-based rational design to optimize antigen presentation and focus antibody (Ab) responses to key epitopes on the pre-fusion (pre-F) protein. This protein was fused to ferritin nanoparticles

  • Regulatory T cells in skin injury: At the crossroads of tolerance and tissue repair.
    Sci. Immunol (IF 13.44) Pub Date : 2020-05-01
    Ian C Boothby,Jarish N Cohen,Michael D Rosenblum