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Reprogramming of acetate metabolism in CD8+ T cells during re-call responses

Applicant Balmer Maria Luisa
Number 171261
Funding scheme Marie Heim-Voegtlin grants
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Immunology, Immunopathology
Start/End 01.11.2017 - 31.10.2020
Approved amount 263'400.00
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All Disciplines (4)

Discipline
Immunology, Immunopathology
Cellular Biology, Cytology
Molecular Biology
Biochemistry

Keywords (4)

Metabolism; Acetate; Immunological memory; CD8+ T cells

Lay Summary (German)

Lead
Zellen unseres Abwehrsystems passen ihren Stoffwechsel den sich laufend ändernden Anforderungen an. In diesem Projekt untersuchen wir, wie die Fettsäure Acetat den Stoffwechsel und die Funktion von Gedächtniszellen während der Immunantwort beeinflusst.
Lay summary

Unser Abwehrsystem ist in der Lage bei wiederholtem Kontakt mit dem gleichen Erreger wesentlich schneller und besser zu reagieren und somit eine erneute Erkrankung zu vermeiden (immunologisches Gedächtnis). Verantwortlich hierfür sind sogenannte Gedächtniszellen.

Wir haben kürzlich gefunden, dass im Rahmen einer Infektion mit Bakterien vermehrt Acetat (eine kurzkettige Fettsäure) gebildet wird. Acetat wird dann von Gedächtniszellen aufgenommen und metabolisiert, was dazu beiträgt dass diese Zellen effizienter funktionieren und Erreger somit rascher eliminiert werden können.

Ziel dieses Projektes ist es, herauszufinden wie Acetat in verschiedenen Stadien der Immunantwort die Gedächtniszellen beeinflusst und dazu beiträgt, dass Mikroorganismen rasch bekämpft werden, ohne aber körpereigenen Zellen zu schädigen. Die Resultate dieser Studie könnten wichtige Hinweise zur Etablierung neuartiger Therapien bei akuten und chronischen Infektionskrankheiten liefern.

Direct link to Lay Summary Last update: 12.09.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
Uncoupling of invasive bacterial mucosal immunogenicity from pathogenicity
Pfister Simona P., Schären Olivier P., Beldi Luca, Printz Andrea, Notter Matheus D., Mukherjee Mohana, Li Hai, Limenitakis Julien P., Werren Joel P., Tandon Disha, Cuenca Miguelangel, Hagemann Stefanie, Uster Stephanie S., Terrazos Miguel A., Gomez de Aguero Mercedes, Schürch Christian M., Coelho Fernanda M., Curtiss Roy, Slack Emma, Balmer Maria L., Hapfelmeier Siegfried (2020), Uncoupling of invasive bacterial mucosal immunogenicity from pathogenicity, in Nature Communications, 11(1), 1978-1978.
Memory CD8+ T Cells Balance Pro- and Anti-inflammatory Activity by Reprogramming Cellular Acetate Handling at Sites of Infection
Balmer Maria L., Ma Eric H., Thompson Andrew J., Epple Raja, Unterstab Gunhild, Lötscher Jonas, Dehio Philippe, Schürch Christian M., Warncke Jan D., Perrin Gaëlle, Woischnig Anne-Kathrin, Grählert Jasmin, Löliger Jordan, Assmann Nadine, Bantug Glenn R., Schären Olivier P., Khanna Nina, Egli Adrian, Bubendorf Lukas, Rentsch Katharina, Hapfelmeier Siegfried, Jones Russell G., Hess Christoph (2020), Memory CD8+ T Cells Balance Pro- and Anti-inflammatory Activity by Reprogramming Cellular Acetate Handling at Sites of Infection, in Cell Metabolism, 32(3), 457-467.e5.
Memory CD8+ T Cells Balance Pro- and Anti-inflammatory Activity by Reprogramming Cellular Acetate Handling at Sites of Infection
Balmer Maria L., Ma Eric H., Thompson Andrew, Epple Raja, Unterstab Gunhild, Lötscher Jonas, Dehio Philippe, Schürch Christian M., Warncke Jan D., Perrin Gaëlle, Woischnig Anne-Kathrin, Grählert Jasmin, Löliger Jordan, Assmann Nadine, Bantug Glenn R., Schären Olivier P., Khanna Nina, Egli Adrian, Bubendorf Lukas, Rentsch Katharina, Hapfelmeier Siegfried, Jones Russell G., Hess Christoph (2020), Memory CD8+ T Cells Balance Pro- and Anti-inflammatory Activity by Reprogramming Cellular Acetate Handling at Sites of Infection, in Cell Metabolism, 1.
Sensing between reactions – how the metabolic microenvironment shapes immunity
Lötscher J., Balmer M. L. (2019), Sensing between reactions – how the metabolic microenvironment shapes immunity, in Clinical {&} Experimental Immunology, 143.

Abstract

The immune system remembers previous encounters with a pathogen, enabling a more rapid and efficient recall response. Memory T cells provide a cellular basis for this key feature of adaptive immunity, and cellular metabolism critically underpins their recall capacity. Tight regulation of the pro-inflammatory, pathogen-directed immune response is required to minimize immunopathology.Recently, we identified that the short-chain fatty acid acetate -which is released into the blood stream during stress conditions such as infection- boosts glycolysis of memory CD8+ T cells, thereby improving their recall-functionality (Balmer et al, 2016).Preliminary data obtained in the meantime now indicate that the timing of acetate-exposure is decisive with regard to its impact on the memory CD8+ T cell function: Whereas acetate boosts memory responses when added prior to T cell receptor stimulation (Balmer et al, 2016), the same metabolite suppressed their effector function when added during cognate activation. In vivo this may reflect acetate exposure of memory cells in transit towards sites of infection/inflammations vs. exposure of these same cells at the site of infection. Notably, in additional preliminary experiments we observed that in memory CD8+ T cells the acetate-assimilation machinery was rapidly downregulated upon antigen-specific stimulation.In this grant submission I propose to elucidate how cognate activation reprograms acetate metabolism in human and murine memory CD8+ T cells. Specifically, I aim to elucidate the molecular/metabolic basis of how the very same metabolite, acetate, mediates opposing outcomes in a context-dependent manner, and to test the immunologic relevance of such reprogramming in vitro and in vivo.
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