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Effects of Interleukin-21 on T cell responses and diseases

Applicant Kopf Manfred
Number 124922
Funding scheme Project funding
Research institution Institut für Integrative Biologie Departement Umweltwissenschaften ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Immunology, Immunopathology
Start/End 01.07.2009 - 30.06.2012
Approved amount 755'000.00
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Keywords (10)

interleukin-21; effector/memory CD8 T cells; regulatory T cells; Th1/Th2/Th17; inflammatory bowel disease; asthma; IL-21; Treg; Th subsets; inflammation

Lay Summary (English)

Lead
Lay summary
CD4+ T helper (Th) cells orchestrate immune responses by differentiating into discrete subsets characterized by distinct cytokine secretion patterns. Th2 cells shape effector responses during allergy and Helminth infections by secretion of a panel of cytokines including IL-4, IL-5, IL-10, and IL-13. Th1 cells mediate control of bacterial, protozoan, and fungal infection by production of IFN-?. Recently a novel subset termed Th17 cells have been shown to mediate organ related auto-immune diseases by production of IL-17. Another population of CD4 T cells with regulatory function (Treg) keeps these CD4 effector T cell subsets in check by secretion of the anti-inflammatory cytokines such IL-10 and TGF-?, or by other yet undefined mechanisms. Cytokines determine not only effector function of T cells subsets but also their fate by inducing lineage specific transcription factors in naïve precursor CD4 T cells. IL-21 is the most recently described member of the type I cytokine family including IL-2, IL-4, IL-7, IL-9, and IL-15; their receptors share the common chain (?c) and signal via the Jak/STAT pathway. These cytokines play crucial roles in T cell responses including cell proliferation, differentiation, and maintaining memory populations, besides their activity on many other cell types of the immune system. Specifically, IL-4 is critical for Th2 cell differentiation and effector responses. IL-7 is required for T cell development and, together with IL-15, in maintenance of memory CD8 T cells. IL-2 is central for tolerance induction by promoting maintenance and function of Treg. Moreover, it is critical for expansion of memory cells following secondary infection. IL-21 has a pleiotropic activity on various T cell subsets including T follicular helper cells (Tfh), Th17, and Th2. In vitro, it has been shown to inhibit differentiation of regulatory T cells (Treg). In addition, IL-21 has also been suggested to promote CD8 T cell responses and to inhibit differentiation of inducible regulatory T cells (Treg). However, it role in control of anti-viral CD8 T cell responses and homeostasis and function of regulatory T cells in vivo remains poorly described. We are currently addressing the roles of IL-21 (i) on regulatory T cells in several inflammatory responses (i.e. colitis) and (ii) during viral infection.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
IL-21 inhibits T cell IL-2 production and impairs Treg homeostasi
Attridge K, Wang CH, Wardzinski L, Kenefeck R, Chamberlain JL, Manzotti C, Kopf M, Walker LS (2012), IL-21 inhibits T cell IL-2 production and impairs Treg homeostasi, in Blood, 119(20), 4656-4664.
IL-21 inhibits T cell IL-2 production and impairs Treg homeostasis.
Attridge Kesley, Wang Chun Jing, Wardzinski Lukasz, Kenefeck Rupert, Chamberlain Jayne L, Manzotti Claire, Kopf Manfred, Walker Lucy S K (2012), IL-21 inhibits T cell IL-2 production and impairs Treg homeostasis., in Blood, 119(20), 4656-64.
Evidence for the divergence of innate and adaptive T-cell precursors before commitment to the αβ and γδ lineages.
Kisielow Jan, Tortola Luigi, Weber Jacqueline, Karjalainen Klaus, Kopf Manfred (2011), Evidence for the divergence of innate and adaptive T-cell precursors before commitment to the αβ and γδ lineages., in Blood, 118(25), 6591-600.
Averting inflammation by targeting the cytokine environment.
Kopf Manfred, Bachmann Martin F, Marsland Benjamin J (2010), Averting inflammation by targeting the cytokine environment., in Nature reviews. Drug discovery, 9(9), 703-18.
Cutting edge: IL-21 and TLR signaling regulate germinal center responses in a B cell-intrinsic manner.
Bessa Juliana, Kopf Manfred, Bachmann Martin F (2010), Cutting edge: IL-21 and TLR signaling regulate germinal center responses in a B cell-intrinsic manner., in Journal of immunology (Baltimore, Md. : 1950), 184(9), 4615-9.
IL-17A/F-signaling does not contribute to the initial phase of mucosal inflammation triggered by S. Typhimurium.
Songhet Pascal, Barthel Manja, Röhn Till A, Van Maele Laurye, Cayet Delphine, Sirard Jean-Claude, Bachmann Martin, Kopf Manfred, Hardt Wolf-Dietrich (2010), IL-17A/F-signaling does not contribute to the initial phase of mucosal inflammation triggered by S. Typhimurium., in PloS one, 5(11), 13804-13804.
IL-21 induces death of marginal zone B cells during chronic inflammation.
Tortola Luigi, Yadava Koshika, Bachmann Martin F, Müller Christoph, Kisielow Jan, Kopf Manfred (2010), IL-21 induces death of marginal zone B cells during chronic inflammation., in Blood, 116(24), 5200-7.
IL-17–producing T cells in lung immunity and inflammation
Kopf Manfred (2009), IL-17–producing T cells in lung immunity and inflammation, in J Allergy Clin Immunol, 123(5), 986-994.
IL-21R on T cells is critical for sustained functionality and control of chronic viral infection.
Fröhlich Anja, Kisielow Jan, Schmitz Iwana, Freigang Stefan, Shamshiev Abdijapar T, Weber Jacqueline, Marsland Benjamin J, Oxenius Annette, Kopf Manfred (2009), IL-21R on T cells is critical for sustained functionality and control of chronic viral infection., in Science (New York, N.Y.), 324(5934), 1576-80.

Collaboration

Group / person Country
Types of collaboration
Martin Bachmann, Cytos Biotechnology, Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Annette Oxenius, Institut für Mikrobiologie, ETH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Lucy Walker, Medical Research Council, University of Birmingham Medical School, Birm Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Summer School on Infection Research Talk given at a conference Cytokines in the regulation of T cell fate and function with a focus on IL-21 20.05.2012 Rügen, Germany, Germany Kopf Manfred;
Kitasato Symposium Talk given at a conference Orchestration of B and T cell responses in health and disease by common gamma chain family cytokines 22.09.2011 Berlin, Germany, Germany Kopf Manfred;
International Hannover Workshop on Cytokine Receptors and Cytokine Signaling Talk given at a conference Regulation of T cell fate and function by cytokines 08.09.2011 Hannover, Germany, Germany Kopf Manfred;
DEWIN Sommer School, DYNAMICS OF HOST-PATHOGEN INTERACTIONS Talk given at a conference Cytokines in the regulation of T cell fate and function with a focus on IL-21 07.07.2011 Potsdam, Germany, Germany Kopf Manfred;
Immunology Spring School Talk given at a conference Cytokines in the regulation of T cell fate and function 13.03.2011 Ettal, Germany Kopf Manfred;
Annual Congress Swiss Association of Allergy and Immunology, Talk given at a conference IL-17-producing T cells in lung immunity and infl ammation 15.04.2010 St. Gallen, Switzerland, Switzerland Kopf Manfred;
World Immune Regulation (WIRM) Talk given at a conference IL-21, a gamma star shedding light on mechanisms of chronic viral infection and asthma 29.03.2010 Davos, Switzerland Kopf Manfred;
Seminar Immunologie und Allergologie (SFB TR22) Talk given at a conference Development and effector mechanisms of T-cell subsets in infection and autoimmunity 07.12.2009 Marburg, Germany Kopf Manfred;
European Congress of Immunology Talk given at a conference Inflammatory Cytokines and Anti-viral Responses 13.09.2009 Berlin, Germany Kopf Manfred;


Self-organised

Title Date Place
Annual joint meeting of the International Cytokine Society and the International Interferon Society 11.09.2012 Geneva, Switzerland
11th International Symposium on Dendritic Cells in Fundamental and Clinical Immunology 26.09.2010 Lugano, Switzerland

Associated projects

Number Title Start Funding scheme
100233 Regulation of immune responses by pro-inflammatory cytokines and co-stimulatory receptors 01.01.2004 Project funding
141175 Control of T cell fate and function in infectious disease by IL-21 and IL-9 01.07.2012 Project funding
139220 Single cell analysis using mass cytometry 01.02.2012 R'EQUIP

Abstract

CD4+ T helper (Th) cells orchestrate immune responses by differentiating into discrete subsets characterized by distinct cytokine secretion patterns. Th2 cells shape effector responses during allergy and Helminth infections by secretion of a panel of cytokines including IL-4, IL-5, IL-10, and IL-13. Th1 cells mediate control of bacterial, protozoan, and fungal infection by production of IFN-?. Recently a novel subset termed Th17 cells have been shown to mediate organ related auto-immune diseases by production of IL-17. Another population of CD4 T cells with regulatory function (Treg) keeps these CD4 effector T cell subsets in check by secretion of the anti-inflammatory cytokines such IL-10 and TGF-ß, or by other yet undefined mechanisms. Cytokines determine not only effector function of T cells subsets but also their fate by inducing lineage specific transcription factors in naïve precursor CD4 T cells. IL-21 is the most recently described member of the type I cytokine family including IL-2, IL-4, IL-7, IL-9, and IL-15; their receptors share the common ?c chain and signal via the Jak/STAT pathway. These cytokines play crucial roles in T cell responses including cell proliferation, differentiation, and maintaining memory populations, besides their activity on many other cell types of the immune system. Specifically, IL-4 is critical for Th2 cell differentiation and effector responses. IL-7 is required for T cell development and, together with IL-15, in maintenance of memory CD8 T cells. IL-2 is central for tolerance induction by promoting maintenance and function of Treg. Moreover, it is critical for expansion of memory cells following secondary rather than primary infection. IL-21 has been shown to promote differentiation and/or responses of Th1, Th2, and Th17 cells dependent on the experimental system, but the results remain relatively controversial. In addition, IL-21 has also been suggested to promote CD8 T cell responses and to inhibit differentiation of inducible regulatory T cells (Treg). However, its role in control of anti-viral CD8 T cell responses and homeostasis and function of regulatory T cells in vivo remains poorly described. We have generated IL-21R-/- mice and initiated studies to 1: Define the role of IL-21/IL-21R in acute and chronic viral infection2: Characterize function of regulatory T cells in IL-21R-/- miceSpecifically, under aim 2, we intend to investigate:2.1: The role of IL-21 in the balance of regulatory T cells and Th2 cells in asthma2.2: The status of regulatory T cells and control of leishmaniasis in the context of IL-21.2.3: The roles of IL-21 vs IL-2 in intestinal homeostasis and inflammation.These studies should provide important data to further understand basic mechanisms of T cell differentiation, effector and memory responses with direct implications for research and therapy of important diseases such as asthma, colitis, and viral infection.
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