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Control of T cell fate and function in infectious disease by IL-21 and IL-9

English title Control of T cell fate and function in infectious disease by IL-21 and IL-9
Applicant Kopf Manfred
Number 141175
Funding scheme Project funding
Research institution Molekulare Gesundheitswissenschaften Departement Biologie ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Immunology, Immunopathology
Start/End 01.07.2012 - 30.06.2015
Approved amount 760'032.00
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Keywords (4)

IL-9 ; IL-21; viral infection; T cell responses

Lay Summary (English)

Lead
Lay summary

The common gamma-chain (gc) cytokines IL-2, IL-7, IL-15, and IL-21 have been shown to determine the short-term and long-term fate of T cell responses during acute and chronic viral infection in some way or other. IL-7 and IL-15 promote homeostatic proliferation of memory cells, IL-2 is essential for CD8 expansion following secondary infection. We and others have shown that IL-21 prevents CD8 T cell exhaustion during chronic viral infection by sustaining long-term functionality of anti-viral CD8 T cell responses. However, a detailed understanding how IL-21 maintains T cell functionality in chronic viral infection remains unclear, especially in light of the finding that IL-21 is dispensable for acute effector, memory, and recall CD8+ T cell responses to infection with viruses that are typically cleared during acute infection. We have evidence that chronic viral infection is associated with the expansion of regulatory T cells (Tregs) and that this is prevented by IL-21. Thus, we are currently studying the roles of Tregs in chronic LCMV infection and the mechanism of their suppression by IL-21. In addition, we will use IL-21reporter mice to visualize dynamics of IL-21 production and to identify IL-21-producing cells during anti-viral responses and other immune responses depending on IL-21 (i.e. Th2-mediated allergic airway inflammation).

The IL-9R also associates with the gc receptor subunit. IL-9 is known to promote defense to gastrointestinal nematodes, anaphylaxis to allergen challenge at mucosal surfaces, and allergic lung inflammation. Few reports also have suggested a role IL-9 in viral infection. Using IL-9 loss-of-function and gain-of-function experiments, we are currently investigating its function in acute and chronic viral infection  

Taken together, these studies will further unravel the role of gc cytokines in determining the fate of T cells and control of acute and chronic viral infection.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Protective effect of a germline, IL-17-neutralizing antibody in murine models of autoimmune inflammatory disease.
Dallenbach Kiran, Maurer Patrik, Röhn Till, Zabel Franziska, Kopf Manfred, Bachmann Martin F (2015), Protective effect of a germline, IL-17-neutralizing antibody in murine models of autoimmune inflammatory disease., in European journal of immunology, 45(4), 1238-47.
T cell lipid peroxidation induces ferroptosis and prevents immunity to infection.
Matsushita Mai, Freigang Stefan, Schneider Christoph, Conrad Marcus, Bornkamm Georg W, Kopf Manfred (2015), T cell lipid peroxidation induces ferroptosis and prevents immunity to infection., in The Journal of experimental medicine, 212(4), 555-68.
The development and function of lung-resident macrophages and dendritic cells.
Kopf Manfred, Schneider Christoph, Nobs Samuel P (2015), The development and function of lung-resident macrophages and dendritic cells., in Nature immunology, 16(1), 36-44.
Alveolar macrophages are essential for protection from respiratory failure and associated morbidity following influenza virus infection.
Schneider Christoph, Nobs Samuel P, Heer Alex K, Kurrer Michael, Klinke Glynis, van Rooijen Nico, Vogel Johannes, Kopf Manfred (2014), Alveolar macrophages are essential for protection from respiratory failure and associated morbidity following influenza virus infection., in PLoS pathogens, 10(4), 1004053-1004053.
Induction of the nuclear receptor PPAR-γ by the cytokine GM-CSF is critical for the differentiation of fetal monocytes into alveolar macrophages.
Schneider Christoph, Nobs Samuel P, Kurrer Michael, Rehrauer Hubert, Thiele Christoph, Kopf Manfred (2014), Induction of the nuclear receptor PPAR-γ by the cytokine GM-CSF is critical for the differentiation of fetal monocytes into alveolar macrophages., in Nature immunology, 15(11), 1026-37.
Influenza A virus uses the aggresome processing machinery for host cell entry.
Banerjee Indranil, Miyake Yasuyuki, Nobs Samuel Philip, Schneider Christoph, Horvath Peter, Kopf Manfred, Matthias Patrick, Helenius Ari, Yamauchi Yohei (2014), Influenza A virus uses the aggresome processing machinery for host cell entry., in Science (New York, N.Y.), 346(6208), 473-7.
siRNA screen of early poxvirus genes identifies the AAA+ ATPase D5 as the virus genome-uncoating factor.
Kilcher Samuel, Schmidt Florian Ingo, Schneider Christoph, Kopf Manfred, Helenius Ari, Mercer Jason (2014), siRNA screen of early poxvirus genes identifies the AAA+ ATPase D5 as the virus genome-uncoating factor., in Cell host & microbe, 15(1), 103-12.
Fatty acid-induced mitochondrial uncoupling elicits inflammasome-independent IL-1α and sterile vascular inflammation in atherosclerosis.
Freigang Stefan, Ampenberger Franziska, Weiss Adrienne, Kanneganti Thirumala-Devi, Iwakura Yoichiro, Hersberger Martin, Kopf Manfred (2013), Fatty acid-induced mitochondrial uncoupling elicits inflammasome-independent IL-1α and sterile vascular inflammation in atherosclerosis., in Nature immunology, 14(10), 1045-53.
IL-21 restricts virus-driven Treg cell expansion in chronic LCMV infection.
Schmitz Iwana, Schneider Christoph, Fröhlich Anja, Frebel Helge, Christ Daniel, Leonard Warren J, Sparwasser Tim, Oxenius Annette, Freigang Stefan, Kopf Manfred (2013), IL-21 restricts virus-driven Treg cell expansion in chronic LCMV infection., in PLoS pathogens, 9(5), 1003362-1003362.
The origin and fate of γδT cell subsets.
Kisielow Jan, Kopf Manfred (2013), The origin and fate of γδT cell subsets., in Current opinion in immunology, 25(2), 181-8.
Psoriasiform dermatitis is driven by IL-36-mediated DC-keratinocyte crosstalk.
Tortola Luigi, Rosenwald Esther, Abel Brian, Blumberg Hal, Schäfer Matthias, Coyle Anthony J, Renauld Jean-Christoph, Werner Sabine, Kisielow Jan, Kopf Manfred (2012), Psoriasiform dermatitis is driven by IL-36-mediated DC-keratinocyte crosstalk., in The Journal of clinical investigation, 122(11), 3965-76.

Collaboration

Group / person Country
Types of collaboration
Prof. Annette Oxenius, Institute of Microbiology, ETH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Jean-Christoph Renauld, Ludwig Institute for Cancer Research, Brussels Belgium (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Charité University Medicine Individual talk Take one and make two - The transcription factor PPARg in development of alveolar macrophages and red pulp macrophages 23.06.2015 Berlin, Germany Kopf Manfred;
FMI Seminar Individual talk Development of alveolar macrophages and their function in respiratory viral infection 19.05.2015 Basel, Switzerland Kopf Manfred;
Pfizer, Seminar Individual talk Development of alveolar macrophages and their function in respiratory viral infection 15.12.2014 Boston, United States of America Kopf Manfred;
Type 2 Immunity Symposium, Cell Press Symposia Talk given at a conference Regulation of type 2 airway responses by ILC1s 10.12.2014 Brugge, Belgium Kopf Manfred;
International Molecular Immunology Meeting Talk given at a conference The glutathione and thioredoxin systems in T cell homeostasis and immunity 28.04.2014 Antalya, Turkey Kopf Manfred;
World Immune Regulation meeting (WIRM) Individual talk PPARγ provides an essential signal downstream of GM-CSF for neonatal terminal differentiation of alveolar macrophage progenitors 22.03.2014 Davos, Switzerland Schneider Christoph;
World Immune Regulation Meeting (WIRM) Talk given at a conference The glutathione and thioredoxin systems in T cell homeostasis and immunity 20.03.2014 Davos, Switzerland Kopf Manfred;
Trinity College Dublin, School of Biochemistry and Immunology - seminar Individual talk Factors regulating alveolar macrophage development and functions during influenza virus infection 05.03.2014 Dublin, Ireland Schneider Christoph;
University Ghent, VIB, Inflammation Research Center, Seminar Individual talk Factors regulating alveolar macrophage development and functions during influenza virus infection 28.02.2014 Ghent, Belgium Schneider Christoph;
Keystone Symposium Poster PPARγ provides an essential signal downstream of GM-CSF for neonatal terminal differentiation of alveolar macrophage progenitors 11.02.2014 Santa Fe, United States of America Schneider Christoph;
Swiss Institute of Allergy and Asthma Research Seminar Individual talk Alveolar Macrophages: Development and Function in Respiratory Viral Infection 23.09.2013 Davos, Switzerland Kopf Manfred;
2nd annual Swiss Psoriasis day Talk given at a conference A crucial role of the IL-36 pathway in the development of psoriasiform inflammation. 01.11.2012 Lausanne, Switzerland Kopf Manfred;
Immunotherapy Symposium Talk given at a conference A crucial role of the IL-36 pathway in the development of psoriasis 08.10.2012 Tübingen, Germany Kopf Manfred;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Treffpunkt ETH Science City German-speaking Switzerland 2013

Awards

Title Year
SNF Early Postdoc Fellowship 2015

Associated projects

Number Title Start Funding scheme
145026 Forward genetic screening in mouse haploid embryonic stem cells (ESCs) to functionally dissect pathways in mammalian development and disease 01.04.2013 R'EQUIP
124922 Effects of Interleukin-21 on T cell responses and diseases 01.07.2009 Project funding

Abstract

Over the past 5 years, cytokines that belong to a subfamily of the type 1 four-helix-bundle cytokines, which all utilize the ?c cytokine receptor in combination with a unique cytokine specific receptor chain including IL-2, IL-7, IL-15, and IL-21, have been shown to determine the short-term and long-term fate of T cell responses in acute and chronic viral infection. IL-7 and IL-15 promote homeostatic proliferation of memory cells, IL-2 is essential for CD8 expansion following secondary infection, and IL-21 prevents CD8 T cell exhaustion during chronic viral infection. A detailed mechanism how IL-21 maintains T cell functionality in chronic viral infection remains unclear, especially in light of the finding that IL-21 is dispensable for acute effector, memory, and recall CD8+ T cell responses to infection with viruses that are typically cleared after the acute response. We have found that chronic viral infection is associated with the expansion of Tregs, which is prevented by IL-21. Thus, we hypothesize that IL-21 protects from T cell exhaustion during chronic infection by suppression of Tregs and propose to: 1: Investigate anti-viral T cell responses and viral clearance in wild-type and IL-21R-/- mice using a Foxp3+ Treg loss-of-function and gain-of-function approach. Notably, CD8+ T cells lacking either the IL-2Ra or the IL-21R show normal expansion, contraction and maintenance of long-term memory following resolved infection. We hypothesize that IL-2 and IL-21 have overlapping activities in the generation of memory T cells and the absence of one can be compensated by the presence of the other. Thus, we propose to:2: Study viral infection in IL-2Ra/IL-21R double-deficient mice.IL-21 can be produced by a variety of T cell subpopulations. To understand the role of IL-21 in immune responses it is important to determine dynamics of IL-21 production and identify IL-21-producing cells. However, measurement of IL-21 is difficult due to low frequency of IL-21 producing cells and low-level production per cell in vivo. To overcome this obstacle, we propose to:3: Generate Bac transgenic IL-21-reporter mice The IL-9R also associates with and signals through the ?c chain. IL-9 is known to promote clearance of gastrointestinal nematodes, anaphylaxis to allergen challenge at mucosal surfaces, and allergic lung inflammation. However, studies on the role of IL-9 in viral infection are scarce. We have observed that IL-9R-/- mice show elevated IFN? and TNFa production throughout the course of resolved and chronic infection with LCMV. Thus we hypothesize that IL-9 interferes with pluripotency of T cell responses and efficient viral clearance. To study this we propose to4: Determine the role of IL-9 in acute and chronic viral infection by IL-9 loss-of-function and gain-of-function experimentsTaken together, these studies will further unravel the role of ?c cytokines in determining the fate of T cells and control of acute and chronic viral infection.
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