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T CELL-INTRINSIC ROLE OF PATTERN RECOGNITION RECEPTORS

English title T CELL-INTRINSIC ROLE OF PATTERN RECOGNITION RECEPTORS
Applicant Guarda Greta
Number 139094
Funding scheme SNSF Professorships
Research institution
Institution of higher education University of Lausanne - LA
Main discipline Immunology, Immunopathology
Start/End 01.08.2012 - 31.07.2016
Approved amount 1'474'318.00
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All Disciplines (3)

Discipline
Immunology, Immunopathology
Biochemistry
Cellular Biology, Cytology

Keywords (6)

T cell; NOD-like receptors (NLRs); RIG-I-like receptors (RLRs); antiviral response; tumor surveillance; antigen presentation

Lay Summary (English)

Lead
Lay summary

The immune system protects us from threatening infections. It does so by means of two lines of defense: the innate and the adaptive immune branches. Innate immune cells express a number of receptors called pattern recognition receptors (PRRs), devoted to the recognition of structures conserved among pathogens. Engagement of these receptors leads to prompt activation of innate immune cells, which fight the infection.

T lymphocytes recognize the pathogen they are specific for through the ‘T cell receptor’, becoming thereby activated. Although slower to develop, adaptive immunity has the advantage to be pathogen-specific and to form a long-lasting response, enabling early protection upon secondary infection. 

Certain PRRs, which are typical of the innate immune system, are however highly expressed by adaptive T lymphocytes an aspect that has been overlooked so far. This proposal aims to evaluate - by using knockout mouse models and biochemical approaches - the T cell-intrinsic role of selected PRRs predominantly expressed and poorly characterized in these lymphocytes.

It is possible that PRRs might provide T lymphocytes with functions resembling that of innate immune cells. Alternatively, certain PRRs might exert novel functions in roles more traditionally associated with T cell biology (adaptive immune system pathways). Both scenarios would be highly relevant to our knowledge of immunology, bringing new insights into important aspects of T lymphocyte responses and suggesting new opportunities for therapeutic intervention.


Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
NLRC5 shields T lymphocytes from NK-cell-mediated elimination under inflammatory conditions
Ludigs Kristina, Jandus Camilla, Utzschneider Daniel T., Staehli Francesco, Bessoles Stéphanie, Dang Anh Thu, Rota Giorgia, Castro Wilson, Zehn Dietmar, Vivier Eric, Held Werner, Romero Pedro, Guarda Greta (2016), NLRC5 shields T lymphocytes from NK-cell-mediated elimination under inflammatory conditions, in Nature Communications, 7, 10554-10554.
NLRC5, a promising new entry in tumor immunology.
Chelbi Sonia, Guarda Greta (2016), NLRC5, a promising new entry in tumor immunology., in J Immunother Cancer, -.
T Cell Priming by Activated Nlrc5-Deficient Dendritic Cells Is Unaffected despite Partially Reduced MHC Class I Levels
Rota G., Ludigs K., Siegert S., Tardivel A., Morgado L., Reith W., De Gassart A., Guarda G. (2016), T Cell Priming by Activated Nlrc5-Deficient Dendritic Cells Is Unaffected despite Partially Reduced MHC Class I Levels, in The Journal of Immunology, 196(7), 2939-2946.
NLRC5 exclusively transactivates MHC class I and related genes through a distinctive SXY module.
Ludigs Kristina, Seguín-Estévez Queralt, Lemeille Sylvain, Ferrero Isabel, Rota Giorgia, Chelbi Sonia, Mattmann Chantal, MacDonald H Robson, Reith Walter, Guarda Greta (2015), NLRC5 exclusively transactivates MHC class I and related genes through a distinctive SXY module., in PLoS genetics, 11(3), 1005088-1005088.
Innate and adaptive effects of inflammasomes on T cell responses.
Dostert Catherine, Ludigs Kristina, Guarda Greta (2013), Innate and adaptive effects of inflammasomes on T cell responses., in Current opinion in immunology, 25(3), 359-65.
Innate receptors for adaptive immunity.
Michallet Marie-Cécile, Rota Giorgia, Maslowski Kendle, Guarda Greta (2013), Innate receptors for adaptive immunity., in Current opinion in microbiology, 16(3), 296-302.
NLRC5, at the Heart of Antigen Presentation.
Neerincx Andreas, Castro Wilson, Guarda Greta, Kufer Thomas A (2013), NLRC5, at the Heart of Antigen Presentation., in Frontiers in immunology, 4, 397-397.
Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation.
Yan Yiqing, Jiang Wei, Spinetti Thibaud, Tardivel Aubry, Castillo Rosa, Bourquin Carole, Guarda Greta, Tian Zhigang, Tschopp Jurg, Zhou Rongbin (2013), Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation., in Immunity, 38(6), 1154-63.
The Nlrp3 inflammasome regulates acute graft-versus-host disease.
Jankovic Dragana, Ganesan Jayanthi, Bscheider Michael, Stickel Natalie, Weber Felix C, Guarda Greta, Follo Marie, Pfeifer Dietmar, Tardivel Aubry, Ludigs Kristina, Bouazzaoui Abdellatif, Kerl Katrin, Fischer Julius C, Haas Tobias, Schmitt-Gräff Annette, Manoharan Anand, Müller Leonard, Finke Jürgen, Martin Stefan F, Gorka Oliver, Peschel Christian, Ruland Jürgen, Idzko Marco, Duyster Justus, Holler Ernst, The Nlrp3 inflammasome regulates acute graft-versus-host disease., in The Journal of experimental medicine.

Collaboration

Group / person Country
Types of collaboration
Dietmar Zehn Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Kate Schroder Australia (Oceania)
- in-depth/constructive exchanges on approaches, methods or results
Pedro Romero Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Walter Reith Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Eric Vivier France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Werner Held Switzerland (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
EMBO Symposium ‘Innate Immunity in Host-Pathogen Interactions’ Talk given at a conference NLRC5: at the interface between adaptive and innate immunity 26.06.2016 Heidelberg, Germany Guarda Greta;
Seminar, Technische Universtität Munich (TUM) Individual talk NLRC5: at the interface between adaptive and innate immunity 23.05.2016 Munich, Germany Guarda Greta;
Annual Congress SSAI/SSORL Talk given at a conference NLRC5 shields T lymphocytes from NK-cell-mediated elimination under inflammatory conditions 28.04.2016 Montreux, Switzerland Dang Anh Thu;
Annual Congress SSAI/SSORL Poster NLRC5 deficiency confers partial resistance to murine leukemia virus infection 28.04.2016 Montreux, Switzerland Castro Wilson;
10th WIRM Talk given at a conference NLRC5 shields T lymphocytes from NK cell-mediated elimination under inflammatory conditions 16.03.2016 Davos, Switzerland Guarda Greta;
Workshop on Cell Death, Immunity and Disease, Zurich, Switzerland Talk given at a conference NLRC5 across adaptive and innate immunity 05.10.2015 Zurich, Switzerland Guarda Greta;
4th European Congress of Immunology Poster Characterization of Nlrc3-deficient mice upon LCMV infection 06.09.2015 Vienna, Austria Dang Anh Thu;
Summer Course in immunology Talk given at a conference Pattern recognition receptors: at the interface between innate and adaptive immunity 31.08.2015 Lausanne, Switzerland Guarda Greta;
Lund University Immunology Seminar Series (LUIS) Individual talk NOD-like receptors – beyond innate immune sensing 25.05.2015 Lund, Sweden Guarda Greta;
10th ENII-EFIS/EJI Summer School Individual talk A role for NLRC5 in lyphoproliferative disorders 12.05.2015 Porto Cervo, Italy Castro Wilson;
10th ENII-EFIS/EJI Summer School Poster Characterization of Nlrc3-deficient mice upon LCMV infection 12.05.2015 Porto Cervo, Italy Dang Anh Thu;
29th EFI Conference Individual talk NOD-like receptors – beyond inflammasomes 28.04.2015 Geneva, Switzerland Guarda Greta;
Annual Congress SGAI-SSAI 2015 Individual talk NOD-like receptors – inflammasomes and beyond 12.03.2015 Basel, Switzerland Guarda Greta;
3rd International Conference on Immune Tolerance Poster A role for NLRC5 in lyphoproliferative disorders 28.09.2014 Amsterdam, Netherlands Castro Wilson;
44th Annual Meeting German Society for Immunology Talk given at a conference NOD-like receptors - inflammasomes and beyond 17.09.2014 Bonn, Germany Guarda Greta;
IRB Alumni Symposium, Bellinzona, Switzerland Talk given at a conference NLRC5 exclusively transactivates MHC class I genes through a unique SXY module 26.05.2014 Bellinzona, Switzerland Guarda Greta;
Wolfsberg meeting Individual talk A role for NLRC5 in lyphoproliferative disorders 14.04.2014 Weinfelden, Switzerland Castro Wilson;
CIG seminars Individual talk NLRC5 – a novel transcriptional regulator of MHC class I 10.03.2014 Lausanne, Switzerland Guarda Greta;
Seminar, Biozentrum Individual talk NOD-like receptors: innate receptors for adaptive immunity 09.12.2013 Basel, Switzerland Guarda Greta;
“Seminars on Drug Discovery and Development” Individual talk Novel roles of NLRs in the immune response: implications in health and disease 27.11.2013 Zurich, Switzerland Guarda Greta;
Dimet course on Molecular Immunology Talk given at a conference NOD-like receptors: innate receptors for adaptive immunity 13.11.2013 Milan, Italy Guarda Greta;
Seminar, Max Planck Institute for Infection Biology Individual talk NOD-like receptors: innate receptors for adaptive immunity 04.11.2013 Berlin, Germany Guarda Greta;
Life Sciences PhD Days of Luxembourg Talk given at a conference NOD-like receptors: innate receptors for adaptive immunity 09.09.2013 Luxembourg, Luxembourg Guarda Greta;
FBM day Talk given at a conference NLRs: innate receptors for adaptive immunity 28.06.2013 Lausanne, Switzerland Guarda Greta;
Seminar, Department of Dermatology, University of Tübingen Individual talk NLRs: innate receptors for adaptive immunity 12.06.2013 Tuebingen, Germany Guarda Greta;
Seminar, Dermatology Department, University Hospital Zurich Individual talk NLRs: innate receptors for adaptive immunity 22.05.2013 Zurich, Switzerland Guarda Greta;
Roche-Nature Medicine Immunology Symposium Poster NLRC5 DEFICIENCY IMPAIRS MHC CLASS I-DEPENDENT LYMPHOCYTE KILLING BY CYTOTOXIC T CELLS 28.04.2013 Buonas, Switzerland , Switzerland Guarda Greta;
Seminar “Cutting Edge Topics: Immunology & Infection Biology” Individual talk NLRC5, a transcriptional regulator of MHC class I genes 18.12.2012 Zurich, Switzerland Guarda Greta;
Seminar, Institute for Medical Microbiology, Immunology and Hygiene, Universitätsklinikum Köln Individual talk NLRC5, a transcriptional regulator of MHC class I genes 05.12.2012 Cologne, Germany Guarda Greta;
Seminar, INSERM U851 unit - Immunity, Infection, Vaccination Individual talk NLRC5, a transcriptional regulator of MHC class I genes 02.10.2012 Lyon, France Guarda Greta;
Life Science Symposium EPFL SV Poster NLRC5 DEFICIENCY IMPAIRS MHC CLASS I-DEPENDENT LYMPHOCYTE KILLING BY CYTOTOXIC T CELLS 29.08.2012 Lausanne, Switzerland , Switzerland Guarda Greta;


Self-organised

Title Date Place
Annual Congress SSAI/SSORL 28.04.2016 Montreux, Switzerland
Jurg Tschopp Memorial Symposium 27.04.2016 Montreux, Switzerland

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Journée Oser tous les métiers (JOM) Workshop 12.11.2015 Lausanne, Epalinges, Switzerland Guarda Greta;
LS2 annual meeting 2014 Talk 04.02.2014 Lausanne, Switzerland Guarda Greta;
Lecturer for the students of the ‘Summer Undergraduate Research Programme’ (FBM, UNIL) Talk 19.07.2013 Lausanne, Switzerland Guarda Greta;


Associated projects

Number Title Start Funding scheme
165833 T CELL-INTRINSIC ROLE OF PATTERN RECOGNITION RECEPTORS 01.08.2016 SNSF Professorships
150799 Advanced analysis of the function of single cells using flow imaging. 01.12.2013 R'EQUIP

Abstract

Antigen presenting cells (APCs) express a number of innate immune receptors called pattern recognition receptors (PRRs), which detect structures associated with invading pathogens or host-derived danger signals. Engagement of these receptors is crucial for the onset of the inflammatory response and for the efficient presentation of foreign antigens to T lymphocytes. It is commonly believed that T cells depend on APCs not only for their cognate activation, but also for the integration of important innate stimuli allowing a tailored response to pathogens. However, specific PRRs are highly expressed by T lymphocytes, an aspect of T cell biology that has been overlooked thus far. It is possible that these PRRs may provide T lymphocytes with functions resembling that of innate immune cells. Alternatively, proteins belonging to the PRR families may exert novel functions in roles more traditionally associated with T cell biology (antigen-specific, adaptive immune system pathways). This proposal aims to evaluate the T cell-intrinsic role of four PRRs; retinoic acid-inducible gene I (RIG-I), NOD-like receptor family member, pyrin domain containing (NLRP) 1, NLR family member, CARD domain containing (NLRC) 3 and NLRC5. These PRRs were selected on the basis of their predominant expression and negligible functional characterization in T lymphocytes. While no consensus exists on the roles of NLRC3 and NLRC5, RIG-I and NLRP1b (one out of three existing murine NLRP1 isoforms) are activated by pathogen-derived molecular patterns. However, it is unclear whether they fulfill such a function in T cells, and available data tend to disprove this hypothesis. We recently found that NLRC5 is not involved in innate sensing, but acts instead as an essential transcriptional regulator of MHCI in resting lymphocytes. As the downregulation of major-histocompatibility complex (MHC) molecules is an established mechanism exploited by transformed or infected cells to evade immunosurveillance, we propose to further explore the role of this NLR in preventing these pathologies, by taking advantage of novel conditional Nlrc5-deficient mice and assessing NLRC5 expression and activity in primary human specimens. NLRC3 is highly homologous to NLRC5 and CIITA, suggesting that it may similarly act as a transcriptional regulator of MHCs. However, its expression is reduced upon treatment with inflammatory stimuli, indicating that it may exert a negative regulatory function, a hypothesis that we will test in the newly generated conditional Nlrc3-deficient mice and by molecular approaches. Intriguingly, NLRP1 is phylogenetically related to the inflammatory family member NLRP3, raising the hypothesis that it may form an innate sensing platform in T cells. Finally, RIG-I expression is particularly elevated in T cells and modulated by TCR triggering. We will therefore address the molecular mechanism and the functional relevance of this previously unrecognized crosstalk between T cell activation and antiviral receptors by using knockout mouse models and biochemical means.As anticipated by our data on NLRC5, we expect that a detailed analysis of PRR function in T cells will reveal unexpected adaptive aspects of PRR signaling, or highlight unappreciated innate features of T lymphocytes. Both scenarios would be equally innovative and relevant to our knowledge of vertebrate immunology. This may lead to a careful reconsideration of our understanding of innate and adaptive immunity, and may provide us with new opportunities for therapeutic intervention.
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