Publications by authors named "Konrad Gronke"

15 Publications

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Group 3 Innate Lymphoid Cells Program a Distinct Subset of IL-22BP-Producing Dendritic Cells Demarcating Solitary Intestinal Lymphoid Tissues.

Immunity 2020 Nov;53(5):1015-1032.e8

Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany; Berlin Institute of Health (BIH), Anna-Louisa-Karsch Strasse 2, 10117 Berlin, Germany; Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum (DRFZ), an institute of the Leibniz Association, 10117 Berlin, Germany. Electronic address:

Solitary intestinal lymphoid tissues such as cryptopatches (CPs) and isolated lymphoid follicles (ILFs) constitute steady-state activation hubs containing group 3 innate lymphoid cells (ILC3) that continuously produce interleukin (IL)-22. The outer surface of CPs and ILFs is demarcated by a poorly characterized population of CD11c cells. Using genome-wide single-cell transcriptional profiling of intestinal mononuclear phagocytes and multidimensional flow cytometry, we found that CP- and ILF-associated CD11c cells were a transcriptionally distinct subset of intestinal cDCs, which we term CIA-DCs. CIA-DCs required programming by CP- and ILF-resident CCR6 ILC3 via lymphotoxin-β receptor signaling in cDCs. CIA-DCs differentially expressed genes associated with immunoregulation and were the major cellular source of IL-22 binding protein (IL-22BP) at steady state. Mice lacking CIA-DC-derived IL-22BP exhibited diminished expression of epithelial lipid transporters, reduced lipid resorption, and changes in body fat homeostasis. Our findings provide insight into the design principles of an immunoregulatory checkpoint controlling nutrient absorption.
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http://dx.doi.org/10.1016/j.immuni.2020.10.012DOI Listing
November 2020

Interleukin-22 protects intestinal stem cells against genotoxic stress.

Nature 2019 02 30;566(7743):249-253. Epub 2019 Jan 30.

Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Environmental genotoxic factors pose a challenge to the genomic integrity of epithelial cells at barrier surfaces that separate host organisms from the environment. They can induce mutations that, if they occur in epithelial stem cells, contribute to malignant transformation and cancer development. Genome integrity in epithelial stem cells is maintained by an evolutionarily conserved cellular response pathway, the DNA damage response (DDR). The DDR culminates in either transient cell-cycle arrest and DNA repair or elimination of damaged cells by apoptosis. Here we show that the cytokine interleukin-22 (IL-22), produced by group 3 innate lymphoid cells (ILC3) and γδ T cells, is an important regulator of the DDR machinery in intestinal epithelial stem cells. Using a new mouse model that enables sporadic inactivation of the IL-22 receptor in colon epithelial stem cells, we demonstrate that IL-22 is required for effective initiation of the DDR following DNA damage. Stem cells deprived of IL-22 signals and exposed to carcinogens escaped DDR-controlled apoptosis, contained more mutations and were more likely to give rise to colon cancer. We identified metabolites of glucosinolates, a group of phytochemicals contained in cruciferous vegetables, to be a widespread source of genotoxic stress in intestinal epithelial cells. These metabolites are ligands of the aryl hydrocarbon receptor (AhR), and AhR-mediated signalling in ILC3 and γδ T cells controlled their production of IL-22. Mice fed with diets depleted of glucosinolates produced only very low levels of IL-22 and, consequently, the DDR in epithelial cells of mice on a glucosinolate-free diet was impaired. This work identifies a homeostatic network protecting stem cells against challenge to their genome integrity by AhR-mediated 'sensing' of genotoxic compounds from the diet. AhR signalling, in turn, ensures on-demand production of IL-22 by innate lymphocytes directly regulating components of the DDR in epithelial stem cells.
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http://dx.doi.org/10.1038/s41586-019-0899-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420091PMC
February 2019

Innate lymphoid cells, mediators of tissue homeostasis, adaptation and disease tolerance.

Immunol Rev 2018 11;286(1):86-101

Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Innate lymphoid cells (ILC) are a recently identified group of tissue-resident innate lymphocytes. Available data support the view that ILC or their progenitors are deposited and retained in tissues early during ontogeny. Thereby, ILC become an integral cellular component of tissues and organs. Here, we will review the intriguing relationships between ILC and basic developmental and homeostatic processes within tissues. Studying ILC has already led to the appreciation of the integral roles of immune cells in tissue homeostasis, morphogenesis, metabolism, regeneration, and growth. This area of immunology has not yet been studied in-depth but is likely to reveal important networks contributing to disease tolerance and may be harnessed for future therapeutic approaches.
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http://dx.doi.org/10.1111/imr.12718DOI Listing
November 2018

Expression of IL-17F is associated with non-pathogenic Th17 cells.

J Mol Med (Berl) 2018 08 29;96(8):819-829. Epub 2018 Jun 29.

University Medical Center of the Johannes Gutenberg University Mainz, Institute for Molecular Medicine, 55131, Mainz, Germany.

IL-17A and IL-17F share the highest sequence homology of the IL-17 family and signal via the same IL-17RA/RC receptor heterodimer. To better explore the expression of these two cytokines, we used a double reporter mouse strain (IL-17 mice), where IL-17A expressing cells are marked by enhanced green fluorescent protein (eGFP) while red fluorescence protein (RFP) reports the expression of IL-17F. In steady state, we found that Th17 and γδ T cells only expressed IL-17A, while IL-17F expression was restricted to CD8 T cells (Tc17) and innate lymphoid cells (ILC type 3) of the gut. In experimental autoimmune encephalomyelitis, the vast majority of CNS-infiltrating Th17 cells expressed IL-17A but not IL-17F. In contrast, anti-CD3-induced, TGF-β-driven Th17 cells in the gut expressed both of these IL-17 cytokines. In line with this, in vitro differentiation of Th17 cells in the presence of IL-1β led primarily to IL-17A expressing T cells, while TGF-β induced IL-17F co-expressing Th17 cells. Our results suggest that expression of IL-17F is associated with non-pathogenic T cells, pointing to a differential function of IL-17A versus IL-17F.

Key Messages: Naïve mice: CD4 T cells and γδ T cells express IL-17A, and Tc17 cells express IL-17F. Gut ILC3 show differential expression of IL17A and F. Th17 differentiation with TGF-β1 induces IL-17A and F, whereas IL-1β induced cells expressing IL-17A. Th17 cells in EAE in CNS express IL-17A only. Gut Th17 cells induced by anti-CD3 express IL-17A and F together as skin γδ T cells of IMQ-treated mice.
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http://dx.doi.org/10.1007/s00109-018-1662-5DOI Listing
August 2018

A catch-22: Interleukin-22 and cancer.

Eur J Immunol 2018 01;48(1):15-31

Institute of Microbiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Barrier surfaces of multicellular organisms are in constant contact with the environment and infractions to the integrity of epithelial surfaces is likely a frequent event. Interestingly, components of the immune system, that can be activated by environmental compounds such as the microbiota or nutrients, are interspersed among epithelial cells or directly underlie the epithelium. It is now appreciated that immune cells continuously receive and integrate signals from the environment. Curiously, such continuous reception of stimulation does not normally trigger an inflammatory response but mediators produced by immune cells in response to such signals seem to rather promote barrier integrity and repair. The molecular mediators involved in this process are poorly understood. In recent years, the cytokine interleukin-22, produced mainly by group 3 innate lymphoid cells (ILCs), has been studied as a paradigm for how immune cells can control various aspects of epithelial cell function because expression of its receptor is restricted to non-hematopoietic cells. We will summarize here the diverse roles of IL-22 for the malignant transformation of epithelial cells, for tumor growth, wound healing and tissue repair. Furthermore, we will discuss IL-22 as a potential therapeutic target.
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http://dx.doi.org/10.1002/eji.201747183DOI Listing
January 2018

The extracellular membrane-proximal domain of membrane-bound IgE restricts B cell activation by limiting B cell antigen receptor surface expression.

Eur J Immunol 2018 03 1;48(3):441-453. Epub 2017 Dec 1.

Institute of Cellular & Molecular Immunology, Unversity Medical Center Göttingen, Göttingen, Germany.

Immunoglobulin E (IgE) antibodies are key mediators of allergic reactions. Due to their potentially harmful anaphylactic properties, their production is tightly regulated. The membrane-bound isoform of IgE (mIgE), which is an integral component of the B cell antigen receptor, has been shown to be critical for the regulation of IgE responses in mice. In primate species including humans, mIgE can be expressed in two isoforms that are produced by alternative splicing of the primary ε Ig heavy chain transcript, and differ in the absence or presence of an extracellular membrane-proximal domain (EMPD) consisting of 52 amino acids. However, the function of the EMPD remains unclear. Here, we demonstrate that the EMPD restricts surface expression of mIgE-containing BCRs in human and murine B cells. The EMPD does not interfere with BCR assembly but acts as an autonomous endoplasmic reticulum retention domain. Limited surface expression of EMPD-containing mIgE-BCRs caused impaired activation of intracellular signaling cascades and hence represents a regulatory mechanism that may control the production of potentially anaphylactic IgE antibodies in primate species.
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http://dx.doi.org/10.1002/eji.201747196DOI Listing
March 2018

A Murine Intestinal Intraepithelial NKp46-Negative Innate Lymphoid Cell Population Characterized by Group 1 Properties.

Cell Rep 2017 05;19(7):1431-1443

Laboratory of Experimental Immunology, Ghent University, 9000 Ghent, Belgium. Electronic address:

The Ly49E receptor is preferentially expressed on murine innate-like lymphocytes, such as epidermal Vγ3 T cells, intestinal intraepithelial CD8αα T lymphocytes, and CD49a liver natural killer (NK) cells. As the latter have recently been shown to be distinct from conventional NK cells and have innate lymphoid cell type 1 (ILC1) properties, we investigated Ly49E expression on intestinal ILC populations. Here, we show that Ly49E expression is very low on known ILC populations, but it can be used to define a previously unrecognized intraepithelial innate lymphoid population. This Ly49E-positive population is negative for NKp46 and CD8αα, expresses CD49a and CD103, and requires T-bet expression and IL-15 signaling for differentiation and/or survival. Transcriptome analysis reveals a group 1 ILC gene profile, different from NK cells, iCD8α cells, and intraepithelial ILC1. Importantly, NKp46CD8ααLy49E cells produce interferon (IFN)-γ, suggesting that this previously unrecognized population may contribute to Th1-mediated immunity.
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http://dx.doi.org/10.1016/j.celrep.2017.04.068DOI Listing
May 2017

Isolation and Flow Cytometry Analysis of Innate Lymphoid Cells from the Intestinal Lamina Propria.

Methods Mol Biol 2017 ;1559:255-265

Research Centre for Immunology and Institute of Medical Microbiology and Hygiene, University Medical Center of the Johannes Gutenberg-University Mainz, Obere Zahlbacher Strasse 67, 55131, Mainz, Germany.

The intestinal mucosa constitutes the biggest surface area of the body. It is constantly challenged by bacteria, commensal and pathogenic, protozoa, and food-derived irritants. In order to maintain homeostasis, a complex network of signaling circuits has evolved that includes contributions of immune cells. In recent years a subset of lymphocytes, which belong to the innate immune system, has caught particular attention. These so-called innate lymphoid cells (ILC) reside within the lamina propria of the small and large intestines and rapidly respond to environmental challenges. They provide immunity to various types of infections but may also contribute to organ homeostasis as they produce factors acting on epithelial cells thereby enhancing barrier integrity. Here, we describe how these cells can be isolated from their environment and provide an in-depth protocol how to visualize the various ILC subsets by flow cytometry.
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http://dx.doi.org/10.1007/978-1-4939-6786-5_17DOI Listing
January 2018

Innate lymphoid cells, precursors and plasticity.

Immunol Lett 2016 11 6;179:9-18. Epub 2016 Jul 6.

Research Centre Immunology, University Medical Centre of the Johannes Gutenberg University Mainz, Obere Zahlbacher Strasse 67, D-55131 Mainz, Germany; Institute of Medical Microbiology and Hygiene, University Medical Centre of the Johannes Gutenberg University Mainz, Obere Zahlbacher Strasse 67, D-55131 Mainz, Germany. Electronic address:

Innate lymphoid cells (ILC) have only recently been recognized as a separate entity of the lymphoid lineage. Their subpopulations share common characteristics in terms of early development and major transcriptional circuitry with their related cousins of the T cell world. It is currently hypothesized that ILCs constitute an evolutionary older version of the lymphoid immune system. They are found at all primary entry points for pathogens such as mucosal surfaces of the lung and gastrointestinal system, the skin and the liver, which is the central contact point for pathogens that breach the intestinal barrier and enter the circulation. There, ILC contribute to the first line defense as well as to organ homeostasis. However, ILC are not only involved in classical defense tasks, but also contribute to the organogenesis of lymphoid organs as well as tissue remodeling and even stem cell regeneration. ILC may, therefore, implement different functions according to their emergence in ontogeny, their development and their final tissue location. We will review here their early development from precursors of the fetal liver and the adult bone marrow as well as their late plasticity in adaptation to their environment.
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http://dx.doi.org/10.1016/j.imlet.2016.07.004DOI Listing
November 2016

Tuft cell-derived IL-25 activates and maintains ILC2.

Immunol Cell Biol 2016 Mar;94(3):221-3

Research Centre for Immunology, University of Mainz Medical Centre, Mainz, Germany.

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http://dx.doi.org/10.1038/icb.2016.10DOI Listing
March 2016

CD14 is a key organizer of microglial responses to CNS infection and injury.

Glia 2016 Apr 18;64(4):635-49. Epub 2015 Dec 18.

Institute of Neuropathology, University of Göttingen, Göttingen, 37075, Germany.

Microglia, innate immune cells of the CNS, sense infection and damage through overlapping receptor sets. Toll-like receptor (TLR) 4 recognizes bacterial lipopolysaccharide (LPS) and multiple injury-associated factors. We show that its co-receptor CD14 serves three non-redundant functions in microglia. First, it confers an up to 100-fold higher LPS sensitivity compared to peripheral macrophages to enable efficient proinflammatory cytokine induction. Second, CD14 prevents excessive responses to massive LPS challenges via an interferon β-mediated feedback. Third, CD14 is mandatory for microglial reactions to tissue damage-associated signals. In mice, these functions are essential for balanced CNS responses to bacterial infection, traumatic and ischemic injuries, since CD14 deficiency causes either hypo- or hyperinflammation, insufficient or exaggerated immune cell recruitment or worsened stroke outcomes. While CD14 orchestrates functions of TLR4 and related immune receptors, it is itself regulated by TLR and non-TLR systems to thereby fine-tune microglial damage-sensing capacity upon infectious and non-infectious CNS challenges.
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http://dx.doi.org/10.1002/glia.22955DOI Listing
April 2016

Regenerative biology: Innate immunity repairs gut lining.

Nature 2015 Dec 9;528(7583):488-9. Epub 2015 Dec 9.

Research Centre for Immunology, University of Mainz Medical Centre, and at the Institute of Medical Microbiology and Hygiene, 55131 Mainz, Germany.

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http://dx.doi.org/10.1038/nature16325DOI Listing
December 2015

Interleukin-12 and -23 Control Plasticity of CD127(+) Group 1 and Group 3 Innate Lymphoid Cells in the Intestinal Lamina Propria.

Immunity 2015 Jul 14;43(1):146-60. Epub 2015 Jul 14.

Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. Electronic address:

Human group 1 ILCs consist of at least three phenotypically distinct subsets, including NK cells, CD127(+) ILC1, and intraepithelial CD103(+) ILC1. In inflamed intestinal tissues from Crohn's disease patients, numbers of CD127(+) ILC1 increased at the cost of ILC3. Here we found that differentiation of ILC3 to CD127(+) ILC1 is reversible in vitro and in vivo. CD127(+) ILC1 differentiated to ILC3 in the presence of interleukin-2 (IL-2), IL-23, and IL-1β dependent on the transcription factor RORγt, and this process was enhanced in the presence of retinoic acid. Furthermore, we observed in resection specimen from Crohn's disease patients a higher proportion of CD14(+) dendritic cells (DC), which in vitro promoted polarization from ILC3 to CD127(+) ILC1. In contrast, CD14(-) DCs promoted differentiation from CD127(+) ILC1 toward ILC3. These observations suggest that environmental cues determine the composition, function, and phenotype of CD127(+) ILC1 and ILC3 in the gut.
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http://dx.doi.org/10.1016/j.immuni.2015.06.019DOI Listing
July 2015

Interferon-λ and interleukin 22 act synergistically for the induction of interferon-stimulated genes and control of rotavirus infection.

Nat Immunol 2015 Jul 25;16(7):698-707. Epub 2015 May 25.

Research Centre Immunology and Institute of Medical Microbiology and Hygiene, University of Mainz Medical Centre, Obere Zahlbacher Strasse 67, D-55131 Mainz, Germany.

The epithelium is the main entry point for many viruses, but the processes that protect barrier surfaces against viral infections are incompletely understood. Here we identified interleukin 22 (IL-22) produced by innate lymphoid cell group 3 (ILC3) as an amplifier of signaling via interferon-λ (IFN-λ), a synergism needed to curtail the replication of rotavirus, the leading cause of childhood gastroenteritis. Cooperation between the receptor for IL-22 and the receptor for IFN-λ, both of which were 'preferentially' expressed by intestinal epithelial cells (IECs), was required for optimal activation of the transcription factor STAT1 and expression of interferon-stimulated genes (ISGs). These data suggested that epithelial cells are protected against viral replication by co-option of two evolutionarily related cytokine networks. These data may inform the design of novel immunotherapy for viral infections that are sensitive to interferons.
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http://dx.doi.org/10.1038/ni.3180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589158PMC
July 2015

Leukocyte-derived IFN-α/β and epithelial IFN-λ constitute a compartmentalized mucosal defense system that restricts enteric virus infections.

PLoS Pathog 2015 Apr 7;11(4):e1004782. Epub 2015 Apr 7.

Institute of Virology, University Medical Center Freiburg, Freiburg, Germany.

Epithelial cells are a major port of entry for many viruses, but the molecular networks which protect barrier surfaces against viral infections are incompletely understood. Viral infections induce simultaneous production of type I (IFN-α/β) and type III (IFN-λ) interferons. All nucleated cells are believed to respond to IFN-α/β, whereas IFN-λ responses are largely confined to epithelial cells. We observed that intestinal epithelial cells, unlike hematopoietic cells of this organ, express only very low levels of functional IFN-α/β receptors. Accordingly, after oral infection of IFN-α/β receptor-deficient mice, human reovirus type 3 specifically infected cells in the lamina propria but, strikingly, did not productively replicate in gut epithelial cells. By contrast, reovirus replicated almost exclusively in gut epithelial cells of IFN-λ receptor-deficient mice, suggesting that the gut mucosa is equipped with a compartmentalized IFN system in which epithelial cells mainly respond to IFN-λ that they produce after viral infection, whereas other cells of the gut mostly rely on IFN-α/β for antiviral defense. In suckling mice with IFN-λ receptor deficiency, reovirus replicated in the gut epithelium and additionally infected epithelial cells lining the bile ducts, indicating that infants may use IFN-λ for the control of virus infections in various epithelia-rich tissues. Thus, IFN-λ should be regarded as an autonomous virus defense system of the gut mucosa and other epithelial barriers that may have evolved to avoid unnecessarily frequent triggering of the IFN-α/β system which would induce exacerbated inflammation.
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http://dx.doi.org/10.1371/journal.ppat.1004782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388470PMC
April 2015