Publications by authors named "Natalio Garbi"

79 Publications

Leukocyte trafficking to the lungs and beyond: lessons from influenza for COVID-19.

Nat Rev Immunol 2021 01 19;21(1):49-64. Epub 2020 Nov 19.

David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). Understanding of the fundamental processes underlying the versatile clinical manifestations of COVID-19 is incomplete without comprehension of how different immune cells are recruited to various compartments of virus-infected lungs, and how this recruitment differs among individuals with different levels of disease severity. As in other respiratory infections, leukocyte recruitment to the respiratory system in people with COVID-19 is orchestrated by specific leukocyte trafficking molecules, and when uncontrolled and excessive it results in various pathological complications, both in the lungs and in other organs. In the absence of experimental data from physiologically relevant animal models, our knowledge of the trafficking signals displayed by distinct vascular beds and epithelial cell layers in response to infection by SARS-CoV-2 is still incomplete. However, SARS-CoV-2 and influenza virus elicit partially conserved inflammatory responses in the different respiratory epithelial cells encountered early in infection and may trigger partially overlapping combinations of trafficking signals in nearby blood vessels. Here, we review the molecular signals orchestrating leukocyte trafficking to airway and lung compartments during primary pneumotropic influenza virus infections and discuss potential similarities to distinct courses of primary SARS-CoV-2 infections. We also discuss how an imbalance in vascular activation by leukocytes outside the airways and lungs may contribute to extrapulmonary inflammatory complications in subsets of patients with COVID-19. These multiple molecular pathways are potential targets for therapeutic interventions in patients with severe COVID-19.
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http://dx.doi.org/10.1038/s41577-020-00470-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675406PMC
January 2021

BATF3 programs CD8 T cell memory.

Nat Immunol 2020 11 28;21(11):1397-1407. Epub 2020 Sep 28.

Würzburg Institute of Systems Immunology, Max-Planck Research Group, University of Würzburg, Würzburg, Germany.

Antiviral CD8 T cell responses are characterized by an initial activation/priming of T lymphocytes followed by a massive proliferation, subset differentiation, population contraction and the development of a stable memory pool. The transcription factor BATF3 has been shown to play a central role in the development of conventional dendritic cells, which in turn are critical for optimal priming of CD8 T cells. Here we show that BATF3 was expressed transiently within the first days after T cell priming and had long-lasting T cell-intrinsic effects. T cells that lacked Batf3 showed normal expansion and differentiation, yet succumbed to an aggravated contraction and had a diminished memory response. Vice versa, BATF3 overexpression in CD8 T cells promoted their survival and transition to memory. Mechanistically, BATF3 regulated T cell apoptosis and longevity via the proapoptotic factor BIM. By programing CD8 T cell survival and memory, BATF3 is a promising molecule to optimize adoptive T cell therapy in patients.
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http://dx.doi.org/10.1038/s41590-020-0786-2DOI Listing
November 2020

Infiltration and Clustering of Major Histocompatibility Complex II Antigen-Presenting Cells in the Skin of Patients with Atopic Dermatitis.

J Invest Dermatol 2021 Apr 6;141(4):939-942. Epub 2020 Sep 6.

Department of Dermatology and Allergy, University of Bonn, Bonn, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2020.07.032DOI Listing
April 2021

A high-salt diet compromises antibacterial neutrophil responses through hormonal perturbation.

Sci Transl Med 2020 03;12(536)

Institute of Experimental Immunology, University Hospital of Bonn, Rheinische Friedrich Wilhelm University, 53127 Bonn, Germany.

The Western diet is rich in salt, which poses various health risks. A high-salt diet (HSD) can stimulate immunity through the nuclear factor of activated T cells 5 (Nfat5)-signaling pathway, especially in the skin, where sodium is stored. The kidney medulla also accumulates sodium to build an osmotic gradient for water conservation. Here, we studied the effect of an HSD on the immune defense against uropathogenic -induced pyelonephritis, the most common kidney infection. Unexpectedly, pyelonephritis was aggravated in mice on an HSD by two mechanisms. First, on an HSD, sodium must be excreted; therefore, the kidney used urea instead to build the osmotic gradient. However, in contrast to sodium, urea suppressed the antibacterial functionality of neutrophils, the principal immune effectors against pyelonephritis. Second, the body excretes sodium by lowering mineralocorticoid production via suppressing aldosterone synthase. This caused an accumulation of aldosterone precursors with glucocorticoid functionality, which abolished the diurnal adrenocorticotropic hormone-driven glucocorticoid rhythm and compromised neutrophil development and antibacterial functionality systemically. Consistently, under an HSD, systemic infection was also aggravated in a glucocorticoid-dependent manner. Glucocorticoids directly induced Nfat5 expression, but pharmacological normalization of renal Nfat5 expression failed to restore the antibacterial defense. Last, healthy humans consuming an HSD for 1 week showed hyperglucocorticoidism and impaired antibacterial neutrophil function. In summary, an HSD suppresses intrarenal neutrophils Nfat5-independently by altering the local microenvironment and systemically by glucocorticoid-mediated immunosuppression. These findings argue against high-salt consumption during bacterial infections.
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http://dx.doi.org/10.1126/scitranslmed.aay3850DOI Listing
March 2020

Splenic Red Pulp Macrophages Cross-Prime Early Effector CTL That Provide Rapid Defense against Viral Infections.

J Immunol 2020 01 27;204(1):87-100. Epub 2019 Nov 27.

Institut für Experimentelle Immunologie, Rheinische Friedrich-Wilhelms-Universität, 53127 Bonn, Germany; and

Cross-presentation allows dendritic cells (DCs) to present peptides derived from endocytosed Ags on MHC class I molecules, which is important for activating CTL against viral infections and tumors. Type 1 classical DCs (cDC1), which depend on the transcription factor Batf3, are considered the main cross-presenting cells. In this study, we report that soluble Ags are efficiently cross-presented also by transcription factor SpiC-dependent red pulp macrophages (RPM) of the spleen. In contrast to cDC1, RPM used the mannose receptor for Ag uptake and employed the proteasome- and TAP-dependent cytosolic cross-presentation pathway, previously shown to be used in vitro by bone marrow-derived DCs. In an in vivo vaccination model, both cDC1 and RPM cross-primed CTL efficiently but with distinct kinetics. Within a few days, RPM induced very early effector CTL of a distinct phenotype (Ly6A/E Ly6C KLRG1 CD127 CXCR1 Grz-B). In an adenoviral infection model, such CTL contained the early viral spread, whereas cDC1 induced short-lived effector CTL that eventually cleared the virus. RPM-induced early effector CTL also contributed to the endogenous antiviral response but not to CTL memory generation. In conclusion, RPM can contribute to antiviral immunity by generating a rapid CTL defense force that contains the virus until cDC1-induced CTL are available to eliminate it. This function can be harnessed for improving vaccination strategies aimed at inducing CTL.
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http://dx.doi.org/10.4049/jimmunol.1900021DOI Listing
January 2020

Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition).

Authors:
Andrea Cossarizza Hyun-Dong Chang Andreas Radbruch Andreas Acs Dieter Adam Sabine Adam-Klages William W Agace Nima Aghaeepour Mübeccel Akdis Matthieu Allez Larissa Nogueira Almeida Giorgia Alvisi Graham Anderson Immanuel Andrä Francesco Annunziato Achille Anselmo Petra Bacher Cosima T Baldari Sudipto Bari Vincenzo Barnaba Joana Barros-Martins Luca Battistini Wolfgang Bauer Sabine Baumgart Nicole Baumgarth Dirk Baumjohann Bianka Baying Mary Bebawy Burkhard Becher Wolfgang Beisker Vladimir Benes Rudi Beyaert Alfonso Blanco Dominic A Boardman Christian Bogdan Jessica G Borger Giovanna Borsellino Philip E Boulais Jolene A Bradford Dirk Brenner Ryan R Brinkman Anna E S Brooks Dirk H Busch Martin Büscher Timothy P Bushnell Federica Calzetti Garth Cameron Ilenia Cammarata Xuetao Cao Susanna L Cardell Stefano Casola Marco A Cassatella Andrea Cavani Antonio Celada Lucienne Chatenoud Pratip K Chattopadhyay Sue Chow Eleni Christakou Luka Čičin-Šain Mario Clerici Federico S Colombo Laura Cook Anne Cooke Andrea M Cooper Alexandra J Corbett Antonio Cosma Lorenzo Cosmi Pierre G Coulie Ana Cumano Ljiljana Cvetkovic Van Duc Dang Chantip Dang-Heine Martin S Davey Derek Davies Sara De Biasi Genny Del Zotto Gelo Victoriano Dela Cruz Michael Delacher Silvia Della Bella Paolo Dellabona Günnur Deniz Mark Dessing James P Di Santo Andreas Diefenbach Francesco Dieli Andreas Dolf Thomas Dörner Regine J Dress Diana Dudziak Michael Dustin Charles-Antoine Dutertre Friederike Ebner Sidonia B G Eckle Matthias Edinger Pascale Eede Götz R A Ehrhardt Marcus Eich Pablo Engel Britta Engelhardt Anna Erdei Charlotte Esser Bart Everts Maximilien Evrard Christine S Falk Todd A Fehniger Mar Felipo-Benavent Helen Ferry Markus Feuerer Andrew Filby Kata Filkor Simon Fillatreau Marie Follo Irmgard Förster John Foster Gemma A Foulds Britta Frehse Paul S Frenette Stefan Frischbutter Wolfgang Fritzsche David W Galbraith Anastasia Gangaev Natalio Garbi Brice Gaudilliere Ricardo T Gazzinelli Jens Geginat Wilhelm Gerner Nicholas A Gherardin Kamran Ghoreschi Lara Gibellini Florent Ginhoux Keisuke Goda Dale I Godfrey Christoph Goettlinger Jose M González-Navajas Carl S Goodyear Andrea Gori Jane L Grogan Daryl Grummitt Andreas Grützkau Claudia Haftmann Jonas Hahn Hamida Hammad Günter Hämmerling Leo Hansmann Goran Hansson Christopher M Harpur Susanne Hartmann Andrea Hauser Anja E Hauser David L Haviland David Hedley Daniela C Hernández Guadalupe Herrera Martin Herrmann Christoph Hess Thomas Höfer Petra Hoffmann Kristin Hogquist Tristan Holland Thomas Höllt Rikard Holmdahl Pleun Hombrink Jessica P Houston Bimba F Hoyer Bo Huang Fang-Ping Huang Johanna E Huber Jochen Huehn Michael Hundemer Christopher A Hunter William Y K Hwang Anna Iannone Florian Ingelfinger Sabine M Ivison Hans-Martin Jäck Peter K Jani Beatriz Jávega Stipan Jonjic Toralf Kaiser Tomas Kalina Thomas Kamradt Stefan H E Kaufmann Baerbel Keller Steven L C Ketelaars Ahad Khalilnezhad Srijit Khan Jan Kisielow Paul Klenerman Jasmin Knopf Hui-Fern Koay Katja Kobow Jay K Kolls Wan Ting Kong Manfred Kopf Thomas Korn Katharina Kriegsmann Hendy Kristyanto Thomas Kroneis Andreas Krueger Jenny Kühne Christian Kukat Désirée Kunkel Heike Kunze-Schumacher Tomohiro Kurosaki Christian Kurts Pia Kvistborg Immanuel Kwok Jonathan Landry Olivier Lantz Paola Lanuti Francesca LaRosa Agnès Lehuen Salomé LeibundGut-Landmann Michael D Leipold Leslie Y T Leung Megan K Levings Andreia C Lino Francesco Liotta Virginia Litwin Yanling Liu Hans-Gustaf Ljunggren Michael Lohoff Giovanna Lombardi Lilly Lopez Miguel López-Botet Amy E Lovett-Racke Erik Lubberts Herve Luche Burkhard Ludewig Enrico Lugli Sebastian Lunemann Holden T Maecker Laura Maggi Orla Maguire Florian Mair Kerstin H Mair Alberto Mantovani Rudolf A Manz Aaron J Marshall Alicia Martínez-Romero Glòria Martrus Ivana Marventano Wlodzimierz Maslinski Giuseppe Matarese Anna Vittoria Mattioli Christian Maueröder Alessio Mazzoni James McCluskey Mairi McGrath Helen M McGuire Iain B McInnes Henrik E Mei Fritz Melchers Susanne Melzer Dirk Mielenz Stephen D Miller Kingston H G Mills Hans Minderman Jenny Mjösberg Jonni Moore Barry Moran Lorenzo Moretta Tim R Mosmann Susann Müller Gabriele Multhoff Luis Enrique Muñoz Christian Münz Toshinori Nakayama Milena Nasi Katrin Neumann Lai Guan Ng Antonia Niedobitek Sussan Nourshargh Gabriel Núñez José-Enrique O'Connor Aaron Ochel Anna Oja Diana Ordonez Alberto Orfao Eva Orlowski-Oliver Wenjun Ouyang Annette Oxenius Raghavendra Palankar Isabel Panse Kovit Pattanapanyasat Malte Paulsen Dinko Pavlinic Livius Penter Pärt Peterson Christian Peth Jordi Petriz Federica Piancone Winfried F Pickl Silvia Piconese Marcello Pinti A Graham Pockley Malgorzata Justyna Podolska Zhiyong Poon Katharina Pracht Immo Prinz Carlo E M Pucillo Sally A Quataert Linda Quatrini Kylie M Quinn Helena Radbruch Tim R D J Radstake Susann Rahmig Hans-Peter Rahn Bartek Rajwa Gevitha Ravichandran Yotam Raz Jonathan A Rebhahn Diether Recktenwald Dorothea Reimer Caetano Reis e Sousa Ester B M Remmerswaal Lisa Richter Laura G Rico Andy Riddell Aja M Rieger J Paul Robinson Chiara Romagnani Anna Rubartelli Jürgen Ruland Armin Saalmüller Yvan Saeys Takashi Saito Shimon Sakaguchi Francisco Sala-de-Oyanguren Yvonne Samstag Sharon Sanderson Inga Sandrock Angela Santoni Ramon Bellmàs Sanz Marina Saresella Catherine Sautes-Fridman Birgit Sawitzki Linda Schadt Alexander Scheffold Hans U Scherer Matthias Schiemann Frank A Schildberg Esther Schimisky Andreas Schlitzer Josephine Schlosser Stephan Schmid Steffen Schmitt Kilian Schober Daniel Schraivogel Wolfgang Schuh Thomas Schüler Reiner Schulte Axel Ronald Schulz Sebastian R Schulz Cristiano Scottá Daniel Scott-Algara David P Sester T Vincent Shankey Bruno Silva-Santos Anna Katharina Simon Katarzyna M Sitnik Silvano Sozzani Daniel E Speiser Josef Spidlen Anders Stahlberg Alan M Stall Natalie Stanley Regina Stark Christina Stehle Tobit Steinmetz Hannes Stockinger Yousuke Takahama Kiyoshi Takeda Leonard Tan Attila Tárnok Gisa Tiegs Gergely Toldi Julia Tornack Elisabetta Traggiai Mohamed Trebak Timothy I M Tree Joe Trotter John Trowsdale Maria Tsoumakidou Henning Ulrich Sophia Urbanczyk Willem van de Veen Maries van den Broek Edwin van der Pol Sofie Van Gassen Gert Van Isterdael René A W van Lier Marc Veldhoen Salvador Vento-Asturias Paulo Vieira David Voehringer Hans-Dieter Volk Anouk von Borstel Konrad von Volkmann Ari Waisman Rachael V Walker Paul K Wallace Sa A Wang Xin M Wang Michael D Ward Kirsten A Ward-Hartstonge Klaus Warnatz Gary Warnes Sarah Warth Claudia Waskow James V Watson Carsten Watzl Leonie Wegener Thomas Weisenburger Annika Wiedemann Jürgen Wienands Anneke Wilharm Robert John Wilkinson Gerald Willimsky James B Wing Rieke Winkelmann Thomas H Winkler Oliver F Wirz Alicia Wong Peter Wurst Jennie H M Yang Juhao Yang Maria Yazdanbakhsh Liping Yu Alice Yue Hanlin Zhang Yi Zhao Susanne Maria Ziegler Christina Zielinski Jakob Zimmermann Arturo Zychlinsky

Eur J Immunol 2019 Oct;49(10):1457-1973

Max Planck Institute for Infection Biology, Berlin, Germany.

These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.
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http://dx.doi.org/10.1002/eji.201970107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350392PMC
October 2019

Charcot-Leyden Crystals Activate the NLRP3 Inflammasome and Cause IL-1β Inflammation in Human Macrophages.

J Immunol 2019 01 17;202(2):550-558. Epub 2018 Dec 17.

Institute of Innate Immunity, University Hospitals, University of Bonn, Bonn 53127, Germany;

Charcot-Leyden crystals (CLCs) are Galectin-10 protein crystals that can form after eosinophils degranulate. CLCs can appear and persist in tissues from patients with eosinophilic disorders, such as asthma, allergic reactions, and fungal and helminthic infections. Despite abundant reports of their occurrence in human disease, the inflammatory potential of CLCs has remained unknown. In this article, we show that CLCs induce the release of the proinflammatory cytokine IL-1β upon their phagocytosis by primary human macrophages in vitro. Chemical inhibition and small interfering RNA knockdown of NLRP3 in primary human macrophages abrogated their IL-1β response to CLCs. Using C57BL/6 ASC-mCitrine transgenic inflammasome reporter mice, we showed that the instillation of CLCs into the lungs promoted the assembly of ASC complexes in infiltrating immune cells (neutrophils and inflammatory monocytes) and resulted in IL-1β accumulation into the bronchoalveolar lavage fluid. Our findings reveal that CLCs are recognized by the NLRP3 inflammasome, which may sustain inflammation that follows eosinophilic inflammatory processes.
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http://dx.doi.org/10.4049/jimmunol.1800107DOI Listing
January 2019

Prolonged IKKβ Inhibition Improves Ongoing CTL Antitumor Responses by Incapacitating Regulatory T Cells.

Cell Rep 2017 Oct;21(3):578-586

Institute of Experimental Immunology, Rheinische Friedrich-Wilhelms-Universität, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany. Electronic address:

Regulatory T cells (Tregs) prevent autoimmunity but limit antitumor immunity. The canonical NF-κB signaling pathway both activates immunity and promotes thymic Treg development. Here, we report that mature Tregs continue to require NF-κB signaling through IκB-kinase β (IKKβ) after thymic egress. Mice lacking IKKβ in mature Tregs developed scurfy-like immunopathology due to death of peripheral FoxP3 Tregs. Also, pharmacological IKKβ inhibition reduced Treg numbers in the circulation by ∼50% and downregulated FoxP3 and CD25 expression and STAT5 phosphorylation. In contrast, activated cytotoxic T lymphocytes (CTLs) were resistant to IKKβ inhibition because other pathways, in particular nuclear factor of activated T cells (NFATc1) signaling, sustained their survival and expansion. In a melanoma mouse model, IKKβ inhibition after CTL cross-priming improved the antitumor response and delayed tumor growth. In conclusion, prolonged IKKβ inhibition decimates circulating Tregs and improves CTL responses when commenced after tumor vaccination, indicating that IKKβ represents a druggable checkpoint.
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http://dx.doi.org/10.1016/j.celrep.2017.09.082DOI Listing
October 2017

Guidelines for the use of flow cytometry and cell sorting in immunological studies.

Authors:
Andrea Cossarizza Hyun-Dong Chang Andreas Radbruch Mübeccel Akdis Immanuel Andrä Francesco Annunziato Petra Bacher Vincenzo Barnaba Luca Battistini Wolfgang M Bauer Sabine Baumgart Burkhard Becher Wolfgang Beisker Claudia Berek Alfonso Blanco Giovanna Borsellino Philip E Boulais Ryan R Brinkman Martin Büscher Dirk H Busch Timothy P Bushnell Xuetao Cao Andrea Cavani Pratip K Chattopadhyay Qingyu Cheng Sue Chow Mario Clerici Anne Cooke Antonio Cosma Lorenzo Cosmi Ana Cumano Van Duc Dang Derek Davies Sara De Biasi Genny Del Zotto Silvia Della Bella Paolo Dellabona Günnur Deniz Mark Dessing Andreas Diefenbach James Di Santo Francesco Dieli Andreas Dolf Vera S Donnenberg Thomas Dörner Götz R A Ehrhardt Elmar Endl Pablo Engel Britta Engelhardt Charlotte Esser Bart Everts Anita Dreher Christine S Falk Todd A Fehniger Andrew Filby Simon Fillatreau Marie Follo Irmgard Förster John Foster Gemma A Foulds Paul S Frenette David Galbraith Natalio Garbi Maria Dolores García-Godoy Jens Geginat Kamran Ghoreschi Lara Gibellini Christoph Goettlinger Carl S Goodyear Andrea Gori Jane Grogan Mor Gross Andreas Grützkau Daryl Grummitt Jonas Hahn Quirin Hammer Anja E Hauser David L Haviland David Hedley Guadalupe Herrera Martin Herrmann Falk Hiepe Tristan Holland Pleun Hombrink Jessica P Houston Bimba F Hoyer Bo Huang Christopher A Hunter Anna Iannone Hans-Martin Jäck Beatriz Jávega Stipan Jonjic Kerstin Juelke Steffen Jung Toralf Kaiser Tomas Kalina Baerbel Keller Srijit Khan Deborah Kienhöfer Thomas Kroneis Désirée Kunkel Christian Kurts Pia Kvistborg Joanne Lannigan Olivier Lantz Anis Larbi Salome LeibundGut-Landmann Michael D Leipold Megan K Levings Virginia Litwin Yanling Liu Michael Lohoff Giovanna Lombardi Lilly Lopez Amy Lovett-Racke Erik Lubberts Burkhard Ludewig Enrico Lugli Holden T Maecker Glòria Martrus Giuseppe Matarese Christian Maueröder Mairi McGrath Iain McInnes Henrik E Mei Fritz Melchers Susanne Melzer Dirk Mielenz Kingston Mills David Mirrer Jenny Mjösberg Jonni Moore Barry Moran Alessandro Moretta Lorenzo Moretta Tim R Mosmann Susann Müller Werner Müller Christian Münz Gabriele Multhoff Luis Enrique Munoz Kenneth M Murphy Toshinori Nakayama Milena Nasi Christine Neudörfl John Nolan Sussan Nourshargh José-Enrique O'Connor Wenjun Ouyang Annette Oxenius Raghav Palankar Isabel Panse Pärt Peterson Christian Peth Jordi Petriz Daisy Philips Winfried Pickl Silvia Piconese Marcello Pinti A Graham Pockley Malgorzata Justyna Podolska Carlo Pucillo Sally A Quataert Timothy R D J Radstake Bartek Rajwa Jonathan A Rebhahn Diether Recktenwald Ester B M Remmerswaal Katy Rezvani Laura G Rico J Paul Robinson Chiara Romagnani Anna Rubartelli Beate Ruckert Jürgen Ruland Shimon Sakaguchi Francisco Sala-de-Oyanguren Yvonne Samstag Sharon Sanderson Birgit Sawitzki Alexander Scheffold Matthias Schiemann Frank Schildberg Esther Schimisky Stephan A Schmid Steffen Schmitt Kilian Schober Thomas Schüler Axel Ronald Schulz Ton Schumacher Cristiano Scotta T Vincent Shankey Anat Shemer Anna-Katharina Simon Josef Spidlen Alan M Stall Regina Stark Christina Stehle Merle Stein Tobit Steinmetz Hannes Stockinger Yousuke Takahama Attila Tarnok ZhiGang Tian Gergely Toldi Julia Tornack Elisabetta Traggiai Joe Trotter Henning Ulrich Marlous van der Braber René A W van Lier Marc Veldhoen Salvador Vento-Asturias Paulo Vieira David Voehringer Hans-Dieter Volk Konrad von Volkmann Ari Waisman Rachael Walker Michael D Ward Klaus Warnatz Sarah Warth James V Watson Carsten Watzl Leonie Wegener Annika Wiedemann Jürgen Wienands Gerald Willimsky James Wing Peter Wurst Liping Yu Alice Yue Qianjun Zhang Yi Zhao Susanne Ziegler Jakob Zimmermann

Eur J Immunol 2017 10;47(10):1584-1797

Maurice Müller Laboratories (DKF), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, University of Bern, Murtenstrasse, Bern.

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http://dx.doi.org/10.1002/eji.201646632DOI Listing
October 2017

Targeting myeloid derived suppressor cells with all-trans retinoic acid is highly time-dependent in therapeutic tumor vaccination.

Oncoimmunology 2017;6(8):e1338995. Epub 2017 Jun 16.

Institute of Molecular Medicine, University Bonn, Germany.

Tumor immune escape is a critical problem which frequently accounts for the failure of therapeutic tumor vaccines. Among the most potent suppressors of tumor immunity are myeloid derived suppressor cells (MDSCs). MDSCs can be targeted by all-trans-retinoic-acid (atRA), which reduced their numbers and increased response rates in several vaccination studies. However, not much is known about the optimal administration interval between atRA and the vaccine as well as about its mode of action. Here we demonstrate in 2 different murine tumor models that mice unresponsive to a therapeutic vaccine harbored higher MDSC numbers than did responders. Application of atRA overcame MDSC-mediated immunosuppression and restored tumor control. Importantly, atRA was protective only when administered 3 d after vaccination (delayed treatment), whereas simultaneous administration even decreased the anti-tumor immune response and reduced survival. When analyzing the underlying mechanisms, we found that delayed, but not simultaneous atRA treatment with vaccination abrogated the suppressive capacity in monocytic MDSCs and instead caused them to upregulate MHC-class-II. Consistently, MDSCs from patients with colorectal carcinoma also failed to upregulate HLA-DR after treatment with TLR-ligation. Overall, we demonstrate that atRA can convert non-responders to responders to vaccination by suppressing MDSCs function and not only by reducing their number. Moreover, we identify a novel, strictly time-dependent mode of action of atRA to be considered during immunotherapeutic protocols in the future.
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http://dx.doi.org/10.1080/2162402X.2017.1338995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593699PMC
June 2017

RIG-I Activation Protects and Rescues from Lethal Influenza Virus Infection and Bacterial Superinfection.

Mol Ther 2017 09 8;25(9):2093-2103. Epub 2017 Jul 8.

Department of Otolaryngology, University Hospital Bonn, 53127 Bonn, Germany.

Influenza A virus infection causes substantial morbidity and mortality in seasonal epidemic outbreaks, and more efficient treatments are urgently needed. Innate immune sensing of viral nucleic acids stimulates antiviral immunity, including cell-autonomous antiviral defense mechanisms that restrict viral replication. RNA oligonucleotide ligands that potently activate the cytoplasmic helicase retinoic-acid-inducible gene I (RIG-I) are promising candidates for the development of new antiviral therapies. Here, we demonstrate in an Mx1-expressing mouse model of influenza A virus infection that a single intravenous injection of low-dose RIG-I ligand 5'-triphosphate RNA (3pRNA) completely protected mice from a lethal challenge with influenza A virus for at least 7 days. Furthermore, systemic administration of 3pRNA rescued mice with pre-established fulminant influenza infection and prevented the fatal effects of a streptococcal superinfection. Type I interferon, but not interferon-λ, was required for the therapeutic effect. Our results suggest that the use of RIG-I activating oligonucleotide ligands has the clinical potential to confine influenza epidemics when a strain-specific vaccine is not yet available and to reduce lethality of influenza in severely infected patients.
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http://dx.doi.org/10.1016/j.ymthe.2017.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589155PMC
September 2017

Flt3 ligand-eGFP-reporter expression characterizes functionally distinct subpopulations of CD150 long-term repopulating murine hematopoietic stem cells.

Eur J Immunol 2017 09 26;47(9):1477-1487. Epub 2017 Jul 26.

Senior Group Lymphocyte Development, Max Planck Institute for Infection Biology, Berlin, Germany.

The pool of hematopoietic stem cells (HSCs) in the bone marrow is a mixture of resting, proliferating, and differentiating cells. Long-term repopulating HSCs (LT-HSC) are routinely enriched as Lin Sca1 c-Kit CD34 Flt3 CD150 CD48 cells. The Flt3 ligand (Flt3L) and its receptor Flt3 are important regulators of HSC maintenance, expansion and differentiation. Using Flt3L-eGFP reporter mice, we show that endogenous Flt3L-eGFP-reporter RNA expression correlates with eGFP-protein expression. This Flt3L-eGFP-reporter expression distinguishes two LT-HSC populations with differences in gene expressions and reconstituting potential. Thus, Flt3L-eGFP-reporter cells are identified as predominantly resting HSCs with long-term repopulating capacities. In contrast, Flt3L-eGFP-reporter cells are in majority proliferating HSCs with only short-term repopulating capacities. Flt3L-eGFP-reporter cells express hypoxia, autophagy-inducing, and the LT-HSC-associated genes HoxB5 and Fgd5, while Flt3L-eGFP-reporter HSCs upregulate genes involved in HSC differentiation. Flt3L-eGFP-reporter cells develop to Flt3L-eGFP-reporter cells in vitro, although Flt3L-eGFP-reporter cells remain Flt3L-eGFP-reporter . CD150 Flt3L-eGFP-reporter cells express either endothelial protein C receptor (EPCR) or CD41, while Flt3L-eGFP-reporter cells do express EPCR but not CD41. Thus, FACS-enrichment of Flt3/ Flt3L-eGFP-reporter negative, Lin CD150 CD48 EPCR CD41 HSCs allows a further 5-fold enrichment of functional LT-HSCs.
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http://dx.doi.org/10.1002/eji.201646730DOI Listing
September 2017

Location, function, and ontogeny of pulmonary macrophages during the steady state.

Pflugers Arch 2017 04 13;469(3-4):561-572. Epub 2017 Mar 13.

VIB Inflammation Research Center, Ghent University, Ghent, Belgium.

The lung is continuously exposed to potentially hazardous environmental challenges in the form of inert material and microbes. Pulmonary macrophages are critical in maintaining a low inflammatory context in the lung to facilitate optimal gas exchange. During infection, however, they mediate the immediate response to invading microorganisms in coordination with epithelial cells and other tissue-resident immune cells including dendritic cells, innate lymphocytes and memory T cells, and pulmonary interstitial macrophages. The balance between pulmonary Mø inhibition and activation is regulated by a complex set of receptors whose activation determines whether macrophages remain quiescent or undergo cellular activation. In addition, pulmonary macrophages perform tissue-specific functions such as surfactant catabolism necessary to prevent alveolar proteinosis and interstitial lung disease. This review summarizes current knowledge on different pulmonary macrophage types with an emphasis on their location, function, and available experimental models to manipulate them. Finally, we review recent developments on the dynamic ontogeny of pulmonary macrophages and how it may affect age-related diseases.
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http://dx.doi.org/10.1007/s00424-017-1965-3DOI Listing
April 2017

Distinct Expression and Function of FcεRII in Human B Cells and Monocytes.

J Immunol 2017 04 8;198(8):3033-3044. Epub 2017 Mar 8.

Department of Dermatology and Allergy, University of Bonn, 53127 Bonn, Germany.

FcεRII is a multifunctional low-affinity IgER that is involved in the pathogenesis of allergic, inflammatory, and neoplastic diseases. Although discrepancies in FcεRII-mediated functions are being increasingly recognized, the consequences of FcεRII activation are not completely understood. In this study, we evaluated the expression of FcεRII on human blood cells and found that it was primarily expressed on monocytes and B cells. Although IL-4 promoted expression of the FcεRIIb isoform on B cells and monocytes, the expression of the FcεRIIa isoform was not dependent on IL-4. Furthermore, FcεRII predominantly bound allergen-IgE complexes on B cells but not on monocytes. FcεRII-mediated allergen-IgE complex uptake by B cells directed Ags to MHC class II-rich compartments. FcεRII-bearing monocytes and B cells expressed high levels of the FcεRII sheddase a disintegrin and metalloproteinase 10, which implies that they are important sources of soluble FcεRII. Moreover, we identified that IgE immune complex stimulation of FcεRII activated intracellular tyrosine phosphorylation via Syk in B cells but not in monocytes. Importantly, FcεRII-mediated signaling by allergen-IgE immune complexes increased IFN-γ production in B cells of allergic patients during the build-up phase of allergen-specific immunotherapy. Together, our results demonstrate that FcεRII mediates cell type-dependent function in allergic reactions. In addition, the results identify a novel allergen-IgE complex/FcεRII/Syk/IFN-γ pathway in allergic responses and suggest that FcεRII may play a role in regulating allergic reactions via modulating IFN-γ production in B cells.
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http://dx.doi.org/10.4049/jimmunol.1601028DOI Listing
April 2017

CD8 T Cells Orchestrate pDC-XCR1 Dendritic Cell Spatial and Functional Cooperativity to Optimize Priming.

Immunity 2017 02 9;46(2):205-219. Epub 2017 Feb 9.

Institute of Experimental Immunology, University Hospital, University of Bonn, 53127 Bonn, Germany. Electronic address:

Adaptive cellular immunity is initiated by antigen-specific interactions between T lymphocytes and dendritic cells (DCs). Plasmacytoid DCs (pDCs) support antiviral immunity by linking innate and adaptive immune responses. Here we examined pDC spatiotemporal dynamics during viral infection to uncover when, where, and how they exert their functions. We found that pDCs accumulated at sites of CD8 T cell antigen-driven activation in a CCR5-dependent fashion. Furthermore, activated CD8 T cells orchestrated the local recruitment of lymph node-resident XCR1 chemokine receptor-expressing DCs via secretion of the XCL1 chemokine. Functionally, this CD8 T cell-mediated reorganization of the local DC network allowed for the interaction and cooperation of pDCs and XCR1 DCs, thereby optimizing XCR1 DC maturation and cross-presentation. These data support a model in which CD8 T cells upon activation create their own optimal priming microenvironment by recruiting additional DC subsets to the site of initial antigen recognition.
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http://dx.doi.org/10.1016/j.immuni.2017.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5362251PMC
February 2017

Independent control of natural killer cell responsiveness and homeostasis at steady-state by CD11c+ dendritic cells.

Sci Rep 2016 12 1;6:37996. Epub 2016 Dec 1.

Center for Hematology and Regenerative Medicine (HERM), Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.

During infection and inflammation, dendritic cells (DC) provide priming signals for natural killer (NK) cells via mechanisms distinct from their antigen processing and presentation functions. The influence of DC on resting NK cells, i.e. at steady-state, is less well studied. We here demonstrate that as early as 1 day after DC depletion, NK cells in naïve mice downregulated the NKG2D receptor and showed decreased constitutive phosphorylation of AKT and mTOR. Subsequently, apoptotic NK cells appeared in the spleen concomitant with reduced NK cell numbers. At 4 days after the onset of DC depletion, increased NK cell proliferation was seen in the spleen resulting in an accumulation of Ly49 receptor-negative NK cells. In parallel, NK cell responsiveness to ITAM-mediated triggering and cytokine stimulation dropped across maturation stages, suggestive of a functional deficiency independent from the homeostatic effect. A role for IL-15 in maintaining NK cell function was supported by a gene signature analysis of NK cell from DC-depleted mice as well as by in vivo DC transfer experiments. We propose that DC, by means of IL-15 transpresentation, are required to maintain not only homeostasis, but also function, at steady-state. These processes appear to be regulated independently from each other.
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http://dx.doi.org/10.1038/srep37996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131354PMC
December 2016

Macrophage-derived nitric oxide initiates T-cell diapedesis and tumor rejection.

Oncoimmunology 2016;5(10):e1204506. Epub 2016 Aug 9.

Tumor Immunology Program, German Cancer Research Center (DKFZ) , Heidelberg, Germany.

In tumor biology, nitric oxide (NO) is generally regarded as an immunosuppressive molecule that impedes T-cell functions and activation of endothelial cells. Contrasting with this view, we here describe a critical role for NO derived from inducible nitric oxide (iNOS)-expressing tumor macrophages in T-cell infiltration and tumor rejection as shown by iNOS gene deletion, inhibition of iNOS, or NO donors. Specifically, macrophage-derived NO was found to induce on tumor vessels adhesion molecules that were required for T-cell extravasation. Experiments with human endothelial cells revealed a bimodal dose-dependent effect of NO. High doses of NO donors were indeed suppressive but lower, more physiological concentrations, induced adhesion molecules in an NFkB-dependent pathway and preferentially activated transcription of genes involved in lymphocyte diapedesis. iNOS macrophages in tumors appear to generate precisely the amount of NO that promotes endothelial activation and T-cell infiltration. These results will be valuable for the development of strategies designed to overcome the paucity of T-cell infiltration into tumors that is a major obstacle in clinical cancer immunotherapy.
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http://dx.doi.org/10.1080/2162402X.2016.1204506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087300PMC
August 2016

CD103+ Kidney Dendritic Cells Protect against Crescentic GN by Maintaining IL-10-Producing Regulatory T Cells.

J Am Soc Nephrol 2016 Nov 1;27(11):3368-3382. Epub 2016 Apr 1.

Institute of Experimental Immunology, University Clinic of the Rheinische Friedrich Wilhelms Universität, Bonn, Germany;

Kidney dendritic cells (DCs) regulate nephritogenic T cell responses. Most kidney DCs belong to the CD11b subset and promote crescentic GN (cGN). The function of the CD103 subset, which represents <5% of kidney DCs, is poorly understood. We studied the role of CD103 DCs in cGN using several lines of genetically modified mice that allowed us to reduce the number of these cells. In all lines, we detected a reduction of FoxP3 intrarenal regulatory T cells (T), which protect against cGN. Mice lacking the transcription factor Batf3 had a more profound reduction of CD103 DCs and T than did the other lines used, and showed the most profound aggravation of cGN. The conditional reduction of CD103 DC numbers by 50% in Langerin-DTR mice halved T numbers, which did not suffice to significantly aggravate cGN. Mice lacking the cytokine Flt3L had fewer CD103 DCs and T than Langerin-DTR mice but exhibited milder cGN than did Batf3 mice presumably because proinflammatory CD11b DCs were somewhat depleted as well. Conversely, Flt3L supplementation increased the number of CD103 DCs and T, but also of proinflammatory CD11b DCs. On antibody-mediated removal of CD11b DCs, Flt3L supplementation ameliorated cGN. Mechanistically, CD103 DCs caused cocultured T cells to differentiate into T and produced the chemokine CCL20, which is known to attract T into the kidney. Our findings show that CD103 DCs foster intrarenal FoxP3 T accumulation, thereby antagonizing proinflammatory CD11b DCs. Thus, increasing CD103 DC numbers or functionality might be advantageous in cGN.
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http://dx.doi.org/10.1681/ASN.2015080873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5084885PMC
November 2016

RAGE Enhances TLR Responses through Binding and Internalization of RNA.

J Immunol 2016 11 19;197(10):4118-4126. Epub 2016 Oct 19.

Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany;

Nucleic acid recognition is an important mechanism that enables the innate immune system to detect microbial infection and tissue damage. To minimize the recognition of self-derived nucleic acids, all nucleic acid-sensing signaling receptors are sequestered away from the cell surface and are activated in the cytoplasm or in endosomes. Nucleic acid sensing in endosomes relies on members of the TLR family. The receptor for advanced glycation end-products (RAGE) was recently shown to bind DNA at the cell surface, facilitating DNA internalization and subsequent recognition by TLR9. In this article, we show that RAGE binds RNA molecules in a sequence-independent manner and enhances cellular RNA uptake into endosomes. Gain- and loss-of-function studies demonstrate that RAGE increases the sensitivity of all ssRNA-sensing TLRs (TLR7, TLR8, TLR13), suggesting that RAGE is an integral part of the endosomal nucleic acid-sensing system.
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http://dx.doi.org/10.4049/jimmunol.1502169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062438PMC
November 2016

Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis.

Immunity 2016 08 9;45(2):389-401. Epub 2016 Aug 9.

Department of Immunology, University of Washington, Seattle, WA 98109, USA; Program of Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Electronic address:

CD8(+) T cells recognizing tumor-specific antigens are detected in cancer patients but are dysfunctional. Here we developed a tamoxifen-inducible liver cancer mouse model with a defined oncogenic driver antigen (SV40 large T-antigen) to follow the activation and differentiation of naive tumor-specific CD8(+) T (TST) cells after tumor initiation. Early during the pre-malignant phase of tumorigenesis, TST cells became dysfunctional, exhibiting phenotypic, functional, and transcriptional features similar to dysfunctional T cells isolated from late-stage human tumors. Thus, T cell dysfunction seen in advanced human cancers may already be established early during tumorigenesis. Although the TST cell dysfunctional state was initially therapeutically reversible, it ultimately evolved into a fixed state. Persistent antigen exposure rather than factors associated with the tumor microenvironment drove dysfunction. Moreover, the TST cell differentiation and dysfunction program exhibited features distinct from T cell exhaustion in chronic infections. Strategies to overcome this antigen-driven, cell-intrinsic dysfunction may be required to improve cancer immunotherapy.
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http://dx.doi.org/10.1016/j.immuni.2016.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119632PMC
August 2016

Inflammasome-Dependent Induction of Adaptive NK Cell Memory.

Immunity 2016 06 7;44(6):1406-21. Epub 2016 Jun 7.

Institute of Molecular Medicine, University Hospital Bonn, Bonn, Germany; Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany. Electronic address:

Monobenzone is a pro-hapten that is exclusively metabolized by melanocytes, thereby haptenizing melanocyte-specific antigens, which results in cytotoxic autoimmunity specifically against pigmented cells. Studying monobenzone in a setting of contact hypersensitivity (CHS), we observed that monobenzone induced a long-lasting, melanocyte-specific immune response that was dependent on NK cells, yet fully intact in the absence of T- and B cells. Consistent with the concept of "memory NK cells," monobenzone-induced NK cells resided in the liver and transfer of these cells conferred melanocyte-specific immunity to naive animals. Monobenzone-exposed skin displayed macrophage infiltration and cutaneous lymph nodes showed an inflammasome-dependent influx of macrophages with a tissue-resident phenotype, coinciding with local NK cell activation. Indeed, macrophage depletion or the absence of the NLRP3 inflammasome, the adaptor protein ASC or interleukin-18 (IL-18) abolished monobenzone CHS, thereby establishing a non-redundant role for the NLRP3 inflammasome as a critical proinflammatory checkpoint in the induction of hapten-dependent memory NK cells.
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http://dx.doi.org/10.1016/j.immuni.2016.05.008DOI Listing
June 2016

CD11c.DTR mice develop a fatal fulminant myocarditis after local or systemic treatment with diphtheria toxin.

Eur J Immunol 2016 08 8;46(8):2028-42. Epub 2016 Jun 8.

Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg-Essen, Essen, Germany.

To assess the role of alveolar macrophages (AMs) during a pulmonary Aspergillus fumigatus infection AMs were depleted by intratracheal application of diphtheria toxin (DTX) to transgenic CD11c.DTR mice prior to fungal infection. Unexpectedly, all CD11c.DTR mice treated with DTX died within 4-5 days, whether being infected with A. fumigatus or not. Despite measurable impact of DTX on lung functional parameters, these constrictions could not explain the high mortality rate. Instead, DTX-treated CD11c.DTR animals developed fulminant myocarditis (FM) characterized by massive leukocyte infiltration and myocardial cell destruction, including central parts of the heart's stimulus transmission system. In fact, standard limb lead ECG recordings of diseased but not healthy mice showed a "Brugada"-like pattern with an abnormally high ST segment pointing to enhanced susceptibility for potential lethal arrhythmias. While CD11c.DTR mice are extensively used for the characterization of CD11c(+) cells, including dendritic cells, several studies have already mentioned adverse side effects following DTX treatment. Our results demonstrate that this limitation is based on severe myocarditis but not on the expected lung constrictions, and has to be taken into consideration if this animal model is used. Based on these properties, however, the CD11c.DTR mouse might serve as useful animal model for FM.
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http://dx.doi.org/10.1002/eji.201546245DOI Listing
August 2016

The Hierarchy of Antigen Delivery.

EBioMedicine 2016 Mar 18;5:7-8. Epub 2016 Feb 18.

Institute of Experimental Immunology, Rheinische Friedrich-Wilhelms University, Sigmund Freud Str. 25, D-53127 Bonn, Germany.

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http://dx.doi.org/10.1016/j.ebiom.2016.02.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816849PMC
March 2016

The induction of human myeloid derived suppressor cells through hepatic stellate cells is dose-dependently inhibited by the tyrosine kinase inhibitors nilotinib, dasatinib and sorafenib, but not sunitinib.

Cancer Immunol Immunother 2016 Mar 19;65(3):273-82. Epub 2016 Jan 19.

Institute of Molecular Medicine, University Bonn, Sigmund-Freud-Straße 25, 53127, Bonn, Germany.

Increased numbers of immunosuppressive myeloid derived suppressor cells (MDSCs) correlate with a poor prognosis in cancer patients. Tyrosine kinase inhibitors (TKIs) are used as standard therapy for the treatment of several neoplastic diseases. However, TKIs not only exert effects on the malignant cell clone itself but also affect immune cells. Here, we investigate the effect of TKIs on the induction of MDSCs that differentiate from mature human monocytes using a new in vitro model of MDSC induction through activated hepatic stellate cells (HSCs). We show that frequencies of monocytic CD14(+)HLA-DR(-/low) MDSCs derived from mature monocytes were significantly and dose-dependently reduced in the presence of dasatinib, nilotinib and sorafenib, whereas sunitinib had no effect. These regulatory effects were only observed when TKIs were present during the early induction phase of MDSCs through activated HSCs, whereas already differentiated MDSCs were not further influenced by TKIs. Neither the MAPK nor the NFκB pathway was modulated in MDSCs when any of the TKIs was applied. When functional analyses were performed, we found that myeloid cells treated with sorafenib, nilotinib or dasatinib, but not sunitinib, displayed decreased suppressive capacity with regard to CD8+ T cell proliferation. Our results indicate that sorafenib, nilotinib and dasatinib, but not sunitinib, decrease the HSC-mediated differentiation of monocytes into functional MDSCs. Therefore, treatment of cancer patients with these TKIs may in addition to having a direct effect on cancer cells also prevent the differentiation of monocytes into MDSCs and thereby differentially modulate the success of immunotherapeutic or other anti-cancer approaches.
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http://dx.doi.org/10.1007/s00262-015-1790-5DOI Listing
March 2016

Inhibitor of NFκB Kinase Subunit 2 Blockade Hinders the Initiation but Aggravates the Progression of Crescentic GN.

J Am Soc Nephrol 2016 07 16;27(7):1917-24. Epub 2015 Nov 16.

Third Medical Department of Clinical Medicine, University Hospital Hamburg Eppendorf, Hamburg, Germany;

The NFκB transcription factor family facilitates the activation of dendritic cells (DCs) and CD4(+) T helper (Th) cells, which are important for protective adaptive immunity. Inappropriate activation of these immune cells may cause inflammatory disease, and NFκB inhibitors are promising anti-inflammatory drug candidates. Here, we investigated whether inhibiting the NFκB-inducing kinase IKK2 can attenuate crescentic GN, a severe DC- and Th cell-dependent kidney inflammatory disease. Prophylactic pharmacologic IKK2 inhibition reduced DC and Th cell activation and ameliorated nephrotoxic serum-induced GN in mice. However, therapeutic IKK2 inhibition during ongoing disease aggravated the nephritogenic immune response and disease symptoms. This effect resulted from the renal loss of regulatory T cells, which have been shown to protect against crescentic GN and which require IKK2. In conclusion, although IKK2 inhibition can suppress the induction of nephritogenic immune responses in vivo, it may aggravate such responses in clinically relevant situations, because it also impairs regulatory T cells and thereby, unleashes preexisting nephritogenic responses. Our findings argue against using IKK2 inhibitors in chronic GN and perhaps, other immune-mediated diseases.
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http://dx.doi.org/10.1681/ASN.2015060699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4926984PMC
July 2016

Group 2 innate lymphoid cells license dendritic cells to potentiate memory TH2 cell responses.

Nat Immunol 2016 Jan 2;17(1):57-64. Epub 2015 Nov 2.

Medical Research Council, Laboratory of Molecular Biology, Cambridge, Cambridgeshire, UK.

Rapid activation of memory CD4(+) T helper 2 (TH2) cells during allergic inflammation requires their recruitment into the affected tissue. Here we demonstrate that group 2 innate lymphoid (ILC2) cells have a crucial role in memory TH2 cell responses, with targeted depletion of ILC2 cells profoundly impairing TH2 cell localization to the lungs and skin of sensitized mice after allergen re-challenge. ILC2-derived interleukin 13 (IL-13) is critical for eliciting production of the TH2 cell-attracting chemokine CCL17 by IRF4(+)CD11b(+)CD103(-) dendritic cells (DCs). Consequently, the sentinel function of DCs is contingent on ILC2 cells for the generation of an efficient memory TH2 cell response. These results elucidate a key innate mechanism in the regulation of the immune memory response to allergens.
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http://dx.doi.org/10.1038/ni.3294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4685755PMC
January 2016

Robust Anti-viral Immunity Requires Multiple Distinct T Cell-Dendritic Cell Interactions.

Cell 2015 Sep 18;162(6):1322-37. Epub 2015 Aug 18.

Institute for Experimental Immunology, University of Bonn, 53105 Bonn, Germany. Electronic address:

Host defense against viruses and intracellular parasites depends on effector CD8(+) T cells, whose optimal clonal expansion, differentiation, and memory properties require signals from CD4(+) T cells. Here, we addressed the role of dendritic cell (DC) subsets in initial activation of the two T cell types and their co-operation. Surprisingly, initial priming of CD4(+) and CD8(+) T cells was spatially segregated within the lymph node and occurred on different DCs with temporally distinct patterns of antigen presentation via MHCI versus MHCII molecules. DCs that co-present antigen via both MHC molecules were detected at a later stage; these XCR1(+) DCs are the critical platform involved in CD4(+) T cell augmentation of CD8(+) T cell responses. These findings delineate the complex choreography of cellular interactions underlying effective cell-mediated anti-viral responses, with implications for basic DC subset biology, as well as for translational application to the development of vaccines that evoke optimal T cell immunity.
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http://dx.doi.org/10.1016/j.cell.2015.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567961PMC
September 2015

Eosinophils orchestrate cancer rejection by normalizing tumor vessels and enhancing infiltration of CD8(+) T cells.

Nat Immunol 2015 Jun 27;16(6):609-17. Epub 2015 Apr 27.

Division of Molecular Immunology, German Cancer Research Center, Heidelberg, Germany.

Tumor-associated eosinophilia is frequently observed in cancer. However, despite numerous studies of patients with cancer and mouse models of cancer, it has remained uncertain if eosinophils contribute to tumor immunity or are mere bystander cells. Here we report that activated eosinophils were essential for tumor rejection in the presence of tumor-specific CD8(+) T cells. Tumor-homing eosinophils secreted chemoattractants that guided T cells into the tumor, which resulted in tumor eradication and survival. Activated eosinophils initiated substantial changes in the tumor microenvironment, including macrophage polarization and normalization of the tumor vasculature, which are known to promote tumor rejection. Thus, our study presents a new concept for eosinophils in cancer that may lead to novel therapeutic strategies.
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http://dx.doi.org/10.1038/ni.3159DOI Listing
June 2015