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Metabolic regulation of the memory CD8+ T cell response

English title Metabolic regulation of the memory CD8+ T cell response
Applicant Hess Christoph
Number 153059
Funding scheme Project funding (Div. I-III)
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Immunology, Immunopathology
Start/End 01.04.2014 - 30.09.2017
Approved amount 678'000.00
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All Disciplines (5)

Discipline
Immunology, Immunopathology
Biochemistry
Cellular Biology, Cytology
Molecular Biology
Genetics

Keywords (4)

immunological memory; effector functionality; human CD8+ T cells; metabolism

Lay Summary (German)

Lead
Metabolische Regulation des immunologischen Gedächtnisses
Lay summary

Unser Immunsystem erinnert sich an durchgemachte Infektionen.  Dieses sogenannte immunologische Gedächtnis erlaubt es uns, bei erneuter Infektion mit dem gleichen Erreger rascher und effizienter zu reagieren.  Wie das immunologische Gedächtnis funktioniert ist nur teilweise verstanden.

Jede zelluläre Funktion ist an spezifische Stoffwechsel-Vorgänge (Metabolismus) geknüpft.  Kürzlich konnte unsere Gruppe zeigen, dass rascher Zucker-Metabolismus der Lymphozyten (Abwehrzellen) eng mit dem effizienten Etablieren einer immunologischen Gedächtnissantwort verknüpft ist.

Wir möchten nun detailliert untersuchen, wie rasche metabolische Adaptation in Lymphozyten die so wichtige Frühphase der immunologischen Gedächtnisantwort reguliert.  Konkret möchten wir (i) die molekularen Mechanismen definieren welche den raschen Zuckerstoffwechsel triggern und (ii) untersuchen wie -vice versa- der Zuckerstoffwechsel die Zellfunktion beeinflusst.  Im weiteren erhoffen wir auch besser verstehen zu lernen, wie (i) mitochondriale Stoffwechselvorgänge die Gedächtnisantwort beeinflussen und (ii) metabolische Veränderungen von Lymphozyten mit der im höheren Alter beobachteten Immunschwächung zusammenhängen.

Direct link to Lay Summary Last update: 01.04.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Complement-Mediated Regulation of Metabolism and Basic Cellular Processes
Hess Christoph, Kemper Claudia (2016), Complement-Mediated Regulation of Metabolism and Basic Cellular Processes, in IMMUNITY, 45(2), 240-254.
Feeling Worn Out? PGC1 alpha to the Rescue for Dysfunctional Mitochondria in T Cell Exhaustion
Balmer Maria L., Hess Christoph (2016), Feeling Worn Out? PGC1 alpha to the Rescue for Dysfunctional Mitochondria in T Cell Exhaustion, Cell Press, Editorial.
Complement-Mediated Regulation of Metabolism and Basic Cellular Processes
Hess Christoph, Kemper Claudia (2016), Complement-Mediated Regulation of Metabolism and Basic Cellular Processes, in Immunity, 45(2), 240-254.
Memory CD8(+) T Cells Require Increased Concentrations of Acetate Induced by Stress for Optimal Function
Balmer Maria L., Ma Eric H., Bantug Glenn R., Grahlert Jasmin, Pfister Simona, Glatter Timo, Jauch Annaise, Dimeloe Sarah, Slack Emma, Dehio Philippe, Krzyzaniak Magdalena A., King Carolyn G., Burgener Anne-Valerie, Fischer Marco, Develioglu Leyla, Belle Reka, Recher Mike, Bonilla Weldy V., Macpherson Andrew J., Hapfelmeier Siegfried, Jones Russell G., Hess Christoph (2016), Memory CD8(+) T Cells Require Increased Concentrations of Acetate Induced by Stress for Optimal Function, in IMMUNITY, 44(6), 1312-1324.
A 'Too Negative' ANA Test Predicts Antibody Deficiency
Recher Mike, Berger Christoph T., Daikeler Thomas, Hess Christoph, Heijnen Ingmar A. F. M. (2016), A 'Too Negative' ANA Test Predicts Antibody Deficiency, in JOURNAL OF CLINICAL IMMUNOLOGY, 36(4), 374-376.
Neglected for too long?-CD8(+) Tregs release NOX2-loaded vesicles to inhibit CD4(+) T cells
Berger Christoph T., Hess Christoph (2016), Neglected for too long?-CD8(+) Tregs release NOX2-loaded vesicles to inhibit CD4(+) T cells, JCI, Editorial.
Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy
Pisarsky Laura, Bill Ruben, Fagiani Ernesta, Dimeloe Sarah, Goosen Ryan William, Hagmann Jorg, Hess Christoph, Christofori Gerhard (2016), Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy, in CELL REPORTS, 15(6), 1161-1174.
Glycolysis and EZH2 boost T cell weaponry against tumors
Bantug Glenn R., Hess Christoph (2016), Glycolysis and EZH2 boost T cell weaponry against tumors, Nature Journals, Nature Immunology.
The Immune-Metabolic Basis of Effector Memory CD4(+) T Cell Function under Hypoxic Conditions
Dimeloe Sarah, Mehling Matthias, Frick Corina, Loeliger Jordan, Bantug Glenn R., Sauder Ursula, Fischer Marco, Belle Reka, Develioglu Leyla, Tay Savas, Langenkamp Anja, Hess Christoph (2015), The Immune-Metabolic Basis of Effector Memory CD4(+) T Cell Function under Hypoxic Conditions, in JOURNAL OF IMMUNOLOGY, 196(1), 106-114.
Protection From Varicella Zoster in Solid Organ Transplant Recipients Carrying Killer Cell Immunoglobulin-Like Receptor B Haplotypes
Schmied Laurent, Terszowski Grzegorz, Gonzalez Asensio, Schmitter Karin, Hirsch Hans H., Garzoni Christian, van Delden Christian, Boggian Katia, Mueller Nicolas J., Berger Christoph, Villard Jean, Manuel Oriol, Meylan Pascal, Hess Christoph, Stern Martin (2015), Protection From Varicella Zoster in Solid Organ Transplant Recipients Carrying Killer Cell Immunoglobulin-Like Receptor B Haplotypes, in TRANSPLANTATION, 99(12), 2651-2655.
Stress-Induced In Vivo Recruitment of Human Cytotoxic Natural Killer Cells Favors Subsets with Distinct Receptor Profiles and Associates with Increased Epinephrine Levels
Bigler Marc B., Egli Simon B., Hysek Cedric M., Hoenger Gideon, Schmied Laurent, Baldin Fabian S., Marquardsen Florian A., Recher Mike, Liechti Matthias E., Hess Christoph, Berger Christoph T. (2015), Stress-Induced In Vivo Recruitment of Human Cytotoxic Natural Killer Cells Favors Subsets with Distinct Receptor Profiles and Associates with Increased Epinephrine Levels, in PLOS ONE, 10(12), n/a.
T cells specific for different latent and lytic viral proteins efficiently control Epstein-Barr virus-transformed B cells
Nowakowska Justyna, Stuehler Claudia, Egli Adrian, Battegay Manuel, Rauser Georg, Bantug Glenn Robert, Brander Christian, Hess Christoph, Khanna Nina (2015), T cells specific for different latent and lytic viral proteins efficiently control Epstein-Barr virus-transformed B cells, in CYTOTHERAPY, 17(9), 1280-1291.
Complement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses
Kolev Martin, Dimeloe Sarah, Le Friec Gaelle, Navarini Alexander, Arbore Giuseppina, Povoleri Giovanni A., Fischer Marco, Belle Reka, Loeliger Jordan, Develioglu Leyla, Bantug Glenn R., Watson Julie, Couzi Lionel, Afzali Behdad, Lavender Paul, Hess Christoph, Kemper Claudia (2015), Complement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses, in IMMUNITY, 42(6), 1033-1047.
Influenza vaccine response profiles are affected by vaccine preparation and preexisting immunity, but not HIV infection
Berger Christoph T., Greiff Victor, Mehling Matthias, Fritz Stefanie, Meier Marc A., Hoenger Gideon, Conen Anna, Recher Mike, Battegay Manuel, Reddy Sai T., Hess Christoph (2015), Influenza vaccine response profiles are affected by vaccine preparation and preexisting immunity, but not HIV infection, in HUMAN VACCINES & IMMUNOTHERAPEUTICS, 11(2), 391-396.
Human regulatory T cells lack the cyclophosphamide-extruding transporter ABCB1 and are more susceptible to cyclophosphamide-induced apoptosis
Dimeloe Sarah, Frick Corina, Fischer Marco, Gubser Patrick M., Razik Leyla, Bantug Glenn R., Ravon Morgane, Langenkamp Anja, Hess Christoph (2014), Human regulatory T cells lack the cyclophosphamide-extruding transporter ABCB1 and are more susceptible to cyclophosphamide-induced apoptosis, in EUROPEAN JOURNAL OF IMMUNOLOGY, 44(12), 3614-3620.

Collaboration

Group / person Country
Types of collaboration
Renato Paro, ETH Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Michael Hall, Basel University Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Associated projects

Number Title Start Funding scheme
135677 Metabolic Aspects of T Cell Memory Formation 01.04.2011 Project funding (Div. I-III)
172848 Role of glucose and serine metabolism in regulating the CD8+ T cell memory response 01.04.2017 Project funding (Div. I-III)

Abstract

The immune system remembers previous encounters with a pathogen, enabling a more rapid and efficient re-call response. Memory T cells provide a cellular basis for this key feature of adaptive immunity, yet the molecular mechanisms governing the cellular memory response remain only partially understood.Memory CD8+ T cells can acquire effector function within hours of an antigenic challenge ('innate-like' response). Recently, we found that activation of human memory CD8+ T cells rapidly triggers enhanced glycolytic flux ('immediate-early glycolytic switch'), which is required for the 'innate-like' kinetics of IFN-gamma production. Additionally, we identified the serine-threonine kinase Akt to play a central role in mediating this metabolic switch.We now propose to further define how immediate-early metabolic reprogramming is controlled in CD8+ T cells, and how metabolic changes are linked to the rapid CD8+ T cell recall response. Specifically, we propose to (i) determine the molecular mechanisms triggering, supporting and regulating immediate-early glycolytic switch, (ii) assess the functionality and role of mitochondria during the early-phase of the recall response, and (iii) broadly define the impact of glucose metabolism on genetic and epigenetic regulation of 'innate-like' CD8+ T cell reactivity. We then aim to translate insight gained from basic experiments to elucidate and differentiate the metabolic signature of immunosenescent (i.e. functionally impaired) CD8+ T cells.
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