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The role of the NF?B-inducing kinase NIK in the development and function of cellular immunity

English title The role of the NF?B-inducing kinase NIK in the development and function of cellular immunity
Applicant Becher Burkhard
Number 146130
Funding scheme Project funding
Research institution Institut für Experimentelle Immunologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Immunology, Immunopathology
Start/End 01.11.2013 - 31.10.2016
Approved amount 562'920.00
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Keywords (6)

inflammation; autoimmunity; experimental autoimmune encephalomyelitis; multiple sclerosis; signal transduction; NFkB signaling

Lay Summary (German)

Lead
Die Rolle der NF-kb Signaltransduktion bei der Entstehung einer Immunantwort
Lay summary

Immunzellen haben die Möglichkeit miteinander zu kommunizieren und so auf angreifende Mikroorganismen zu reagieren. sobald also eine Immunantwort entsteht kommt es zu einer Kaskade von Informationsflüssen, welche dazu dienen soll den Körper und die Organe zu schützen. Die Kommunikation zwischen Immunzellen ist dabei essentiell und nach dem Austausch von Signalen zwischen den einzelnen Immunzellen kommt es zu biochemischen Signalprozessen innerhalb der Zellen. Wir interessieren uns insbesondere für einen solchen Signalweg, welcher zumindest für das Immunsystem weitgehend unerforscht ist. Dazu haben wir eine transgene Maus hergestellt, in der wir den Signalweg in einzelnen Zellen spezifisch und irreversibel blockieren können. So können wir dann dessen Funktion bei der Entstehung einer Immunantwort systematisch analysieren. Auf diese Weise wird es dann auch möglich sein diesen Signalweg auch in Patienten mit chronischen Erkrankungen zu manipulieren und therapeutisch anzuwenden.


Direct link to Lay Summary Last update: 12.04.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
BAFF-secreting neutrophils drive plasma cell responses during emergency granulopoiesis.
Parsa Roham, Lund Harald, Georgoudaki Anna-Maria, Zhang Xing-Mei, Ortlieb Guerreiro-Cacais André, Grommisch David, Warnecke Andreas, Croxford Andrew L, Jagodic Maja, Becher Burkhard, Karlsson Mikael C I, Harris Robert A (2016), BAFF-secreting neutrophils drive plasma cell responses during emergency granulopoiesis., in The Journal of experimental medicine, 213(8), 1537-53.
T cell-specific inactivation of mouse CD2 by CRISPR/Cas9.
Beil-Wagner Jane, Dössinger Georg, Schober Kilian, vom Berg Johannes, Tresch Achim, Grandl Martina, Palle Pushpalatha, Mair Florian, Gerhard Markus, Becher Burkhard, Busch Dirk H, Buch Thorsten (2016), T cell-specific inactivation of mouse CD2 by CRISPR/Cas9., in Scientific reports, 6, 21377-21377.
The Good, the Bad, or the Pretty: IL-17 Builds Lymphoid Tissues in the Brain.
Becher Burkhard (2016), The Good, the Bad, or the Pretty: IL-17 Builds Lymphoid Tissues in the Brain., in Immunity, 43(6), 1033-4.
The NFκB-inducing kinase is essential for the developmental programming of skin-resident and IL-17-producing γδ T cells.
Mair Florian, Joller Stefanie, Hoeppli Romy, Onder Lucas, Hahn Matthias, Ludewig Burkhard, Waisman Ari, Becher Burkhard (2016), The NFκB-inducing kinase is essential for the developmental programming of skin-resident and IL-17-producing γδ T cells., in eLife, 4, 8.
Alternative NF-κB signaling regulates mTEC differentiation from podoplanin-expressing presursors in the cortico-medullary junction.
Onder Lucas, Nindl Veronika, Scandella Elke, Chai Qian, Cheng Hung-Wei, Caviezel-Firner Sonja, Novkovic Mario, Bomze David, Maier Reinhard, Mair Florian, Ledermann Birgit, Becher Burkhard, Waisman Ari, Ludewig Burkhard (2015), Alternative NF-κB signaling regulates mTEC differentiation from podoplanin-expressing presursors in the cortico-medullary junction., in European journal of immunology, 45(8), 2218-31.
Astrocyte Depletion Impairs Redox Homeostasis and Triggers Neuronal Loss in the Adult CNS.
Schreiner Bettina, Romanelli Elisa, Liberski Pawel, Ingold-Heppner Barbara, Sobottka-Brillout Bettina, Hartwig Tom, Chandrasekar Vijay, Johannssen Helge, Zeilhofer Hanns Ulrich, Aguzzi Adriano, Heppner Frank, Kerschensteiner Martin, Becher Burkhard (2015), Astrocyte Depletion Impairs Redox Homeostasis and Triggers Neuronal Loss in the Adult CNS., in Cell reports, 12(9), 1377-84.
Contemplating autoimmunity in the Aegean islands.
Walker Lucy S K, Ziegler Steven, Becher Burkhard (2015), Contemplating autoimmunity in the Aegean islands., in Nature immunology, 17(3), 218-20.
Dermal IL-17-producing γδ T cells establish long-lived memory in the skin.
Hartwig Tom, Pantelyushin Stanislav, Croxford Andrew L, Kulig Paulina, Becher Burkhard (2015), Dermal IL-17-producing γδ T cells establish long-lived memory in the skin., in European journal of immunology, 45(11), 3022-33.
GM-CSF in Neuroinflammation: Licensing Myeloid Cells for Tissue Damage.
Croxford Andrew L, Spath Sabine, Becher Burkhard (2015), GM-CSF in Neuroinflammation: Licensing Myeloid Cells for Tissue Damage., in Trends in immunology, 36(10), 651-62.
Immune attack: the role of inflammation in Alzheimer disease.
Heppner Frank L, Ransohoff Richard M, Becher Burkhard (2015), Immune attack: the role of inflammation in Alzheimer disease., in Nature reviews. Neuroscience, 16(6), 358-72.
Innate and adaptive immune responses in the CNS.
Waisman Ari, Liblau Roland S, Becher Burkhard (2015), Innate and adaptive immune responses in the CNS., in The Lancet. Neurology, 14(9), 945-55.
NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis.
Boutaffala L, Bertrand M J M, Remouchamps C, Seleznik G, Reisinger F, Janas M, Bénézech C, Fernandes M T, Marchetti S, Mair F, Ganeff C, Hupalowska A, Ricci J-E, Becher B, Piette J, Knolle P, Caamano J, Vandenabeele P, Heikenwalder M, Dejardin E (2015), NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis., in Cell death and differentiation, 22(12), 2020-33.
Perspectives on cytokine-directed therapies in multiple sclerosis.
Schreiner Bettina, Becher Burkhard (2015), Perspectives on cytokine-directed therapies in multiple sclerosis., in Swiss medical weekly, 145, 14199-14199.
The Cytokine GM-CSF Drives the Inflammatory Signature of CCR2+ Monocytes and Licenses Autoimmunity.
Croxford Andrew L, Lanzinger Margit, Hartmann Felix J, Schreiner Bettina, Mair Florian, Pelczar Pawel, Clausen Björn E, Jung Steffen, Greter Melanie, Becher Burkhard (2015), The Cytokine GM-CSF Drives the Inflammatory Signature of CCR2+ Monocytes and Licenses Autoimmunity., in Immunity, 43(3), 502-14.
The end of gating? An introduction to automated analysis of high dimensional cytometry data.
Mair Florian, Hartmann Felix J, Mrdjen Dunja, Tosevski Vinko, Krieg Carsten, Becher Burkhard (2015), The end of gating? An introduction to automated analysis of high dimensional cytometry data., in European journal of immunology, 46(1), 34-43.
High-dimensional analysis of the murine myeloid cell system.
Becher Burkhard, Schlitzer Andreas, Chen Jinmiao, Mair Florian, Sumatoh Hermi R, Teng Karen Wei Weng, Low Donovan, Ruedl Christiane, Riccardi-Castagnoli Paola, Poidinger Michael, Greter Melanie, Ginhoux Florent, Newell Evan W (2014), High-dimensional analysis of the murine myeloid cell system., in Nature immunology, 15(12), 1181-9.
Innate lymphoid cells regulate intestinal epithelial cell glycosylation.
Goto Yoshiyuki, Obata Takashi, Kunisawa Jun, Sato Shintaro, Ivanov Ivaylo I, Lamichhane Aayam, Takeyama Natsumi, Kamioka Mariko, Sakamoto Mitsuo, Matsuki Takahiro, Setoyama Hiromi, Imaoka Akemi, Uematsu Satoshi, Akira Shizuo, Domino Steven E, Kulig Paulina, Becher Burkhard, Renauld Jean-Christophe, Sasakawa Chihiro, Umesaki Yoshinori, Benno Yoshimi, Kiyono Hiroshi (2014), Innate lymphoid cells regulate intestinal epithelial cell glycosylation., in Science (New York, N.Y.), 345(6202), 1254009-1254009.
Multiple sclerosis-associated IL2RA polymorphism controls GM-CSF production in human TH cells.
Hartmann Felix J, Khademi Mohsen, Aram Jehan, Ammann Sandra, Kockum Ingrid, Constantinescu Cris, Gran Bruno, Piehl Fredrik, Olsson Tomas, Codarri Laura, Becher Burkhard (2014), Multiple sclerosis-associated IL2RA polymorphism controls GM-CSF production in human TH cells., in Nature communications, 5, 5056-5056.
T cell contamination in flow cytometry gating approaches for analysis of innate lymphoid cells.
Burkhard Sara H, Mair Florian, Nussbaum Kathrin, Hasler Sabrina, Becher Burkhard (2014), T cell contamination in flow cytometry gating approaches for analysis of innate lymphoid cells., in PloS one, 9(4), 94196-94196.
Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell-mediated glioma rejection.
Vom Berg Johannes, Vrohlings Melissa, Haller Sergio, Haimovici Aladin, Kulig Paulina, Sledzinska Anna, Weller Michael, Becher Burkhard (2013), Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell-mediated glioma rejection., in The Journal of experimental medicine, 210(13), 2803-11.
TGF-β signalling is required for CD4⁺ T cell homeostasis but dispensable for regulatory T cell function.
Sledzińska Anna, Hemmers Saskia, Mair Florian, Gorka Oliver, Ruland Jürgen, Fairbairn Lynsey, Nissler Anja, Müller Werner, Waisman Ari, Becher Burkhard, Buch Thorsten (2013), TGF-β signalling is required for CD4⁺ T cell homeostasis but dispensable for regulatory T cell function., in PLoS biology, 11(10), 1001674-1001674.
Thy1+ Sca1+ innate lymphoid cells infiltrate the CNS during autoimmune inflammation, but do not contribute to disease development.
Mair Florian, Becher Burkhard (2013), Thy1+ Sca1+ innate lymphoid cells infiltrate the CNS during autoimmune inflammation, but do not contribute to disease development., in European journal of immunology, 44(1), 37-45.

Collaboration

Group / person Country
Types of collaboration
Ari Waisman, Inst. experimental Medicine, University of Mainz Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Associated projects

Number Title Start Funding scheme
116070 The role of lymphoid structures and NF-kB2 signaling in the development of immunization-induced autoimmune disease 01.05.2007 Project funding
131091 The role of noncanonical NF-kB signaling in the development of autoimmune inflammation 01.11.2010 Project funding
136205 Homogeneous photocatalytic water splitting 01.10.2011 Sinergia
170320 The role of the NF-kappa B inducing kinase NIK in central T cell tolerance and peripheral immune regulation 01.11.2016 Project funding
150768 The use of Mass-cytometry in multi-parameter immune cell analysis 01.12.2013 R'EQUIP

Abstract

The NF?B transcription factors consist of a family of five proteins, which can form different NF?B nuclear binding protein complexes. The signal transduction leading to the activation of NF?B’s have been classified into two distinct pathways, namely the canonical, classical pathway and a non-canonical, alternative NF?B pathway. The activity of the canonical NF?B pathway influences cell growth, development, homeostasis, cancer and inflammation. In contrast, the non-canonical pathway has much more discrete effects and its impact on the function of cells and tissues is restricted to very specific functions of the immune system. Central to non-canonical signaling is the NF?B-inducing kinase (NIK). NIK his activated through signaling via members of the TNFR superfamily. In particular the requirement of NIK in LTßR-signaling is highlighted by the developmental malformations in NIKaly/aly and NIK-/- mice, which are alymphoplastic. NIK is vital for the function of lymphoid tissue inducer cells (LTI) and the formation of a lymphoid anlage. NIK-mutant mice are highly immunodeficient and the past funding cycle was used primarily to separate the structural impact of NIK signaling from the intrinsic function of NIK in immune cells. We reported that the immunodeficiency of aly mice results from the impact of NIK on T cell function and not from the lack of SLTs. Conversely, NIK-mediated signal transduction plays a pivotal role in the pathogenesis of autoimmune disease and T cell function and whereas we have identified a role of NIK in APCs during thymocyte development, the precise mechanistic underpinnings are unclear and form the basis of this proposal. Central to this proposal is also a new mouse strain, which we have generated to permit the conditional ablation of the NIK-gene in mice. Specifically, we propose to i) study the role of NIK signaling in the development of lymphoid tissues and cell-mediated immunity, ii) identify the role of NIK in thymic epithelial cells for expression of AIRE and the establishment of central tolerance and iii) to systematically characterize of the impact of disturbed NIK signaling on ?d T cell subsets.
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