Auswirkung mitochondrialer Signal- und Stoffwechselwege auf die durch Dendritische Zellen vermittelte adaptive Immunantwort
Zellbiologie
Zusammenfassung der Projektergebnisse
Adapkve immunity is based on specialized immune cells such as dendrikc cells and T cells. These cells undergo significant changes when they are ackvated. Dendrikc cells become mobile and migrate to the lymph nodes, while T cells enter a highly ackve state and divide rapidly. These changes are accompanied by ships in cellular metabolism, which is crucial for meekng energy needs. Recent research highlights the close link between immune cell funckon and metabolism, parkcularly in T cells. Understanding these metabolic parkcularikes offers hope for intervenkons to modulate immune cells. Our aim was to inveskgate how mitochondrial funckon affect the differenkakon and funckon of dendrikc cells and CD8+ T cells. Mitochondria play a central role in cellular metabolism, but their specific funckonal state in immune cells remained unclear. By studying mitochondrial signaling and metabolism, we aimed to uncover mechanisms underlying immune cell plaskcity and fate decisions. Specific objeckves included determining how mitochondria proteckng mechanisms contribute to adapkve immunity mediated by dendrikc cells and inveskgakng the effects of mitochondrial dysfunckon on dendrikc cell and T cell funckon. In addikon, the project aimed to inveskgate the role of mitochondrial homeostasis during Listeria monocytogenes infeckon. In the first part of the project, we inveskgated how certain genes related to the mitochondrial stress response affect T cell funckon, focusing on GCN2, ATF5 and Surf1. By reducing their expression, we found that they did not significantly affect CD8+ T cell behavior. In contrast, inhibikon of LONP1 led to a reduckon in T cell blaskng and proliferakon, indicakng its importance in metabolic adaptakon. Intereskngly, inhibikon of LONP1 led to a compensatory upregulakon of ATF5, suggeskng a link between these molecules. Overall, our results emphasize the importance of LONP1 for T cell metabolism and funckon and provide insights for further research in this area. Ackvakon of dendrikc cells also leads to metabolic changes, including mitochondrial remodeling and stress responses. To maintain mitochondrial health under stress, cells ackvate the mitochondrial unfolded protein response (UPRmt). This response involves the upregulakon of proteckve proteins such as LONP1 and ATF5. While the role of UPRmt in innate immunity is known, its impact on adapkve immunity remains in large parts unclear. We inveskgated how mitochondrial stress affects DCs. Our studies revealed that disrupkon of the electron transport chain (ETC) leads to DC ackvakon. Similarly, inhibikon of ATP synthase led to the expression of UPRmt markers. However, DCs lacking GCN2, showed no significant differences in funckon or phenotype. We believe that understanding the role of GCN2 in maintaining mitochondrial in DCs lead the way for controlled manipulakons of DC funckon. Mitochondria integrity is also highly crikcal for CD8+ T cells, which have very high energy need following their ackvakon. We tested the inhibitor teriflunomide, which targets elements of the electron transport chain (ETC) and inhibits pyrimidine de novo synthesis, in T cells. We discovered that leflunomide seleckvely affects effector T cells without diminishing memory T cell numbers and funckon. We show that this occurs during early T cell expansion, when effector cells proliferate rapidly but have lower pyrimidine synthesis. We have found that we can control the formakon of effector T cells without damaging memory T cells by targekng pyrimidine levels. This finding offers a new way to safely influence T cell responses. Since targekng pyrimidine synthesis has been shown to be effeckve in autoimmune diseases, this approach holds great promise for future therapies. By pursuing these goals, we have made significant progress in elucidakng the role of mitochondria in CD8+ T cell and DC biology. We are confident that our research will reveal innovakve pathways for the design of immunotherapies and has the potenkal to provide insights for the development of drugs and therapies designed to manipulate specific aspects of adapkve immunity.
Projektbezogene Publikationen (Auswahl)
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Mastering an exhausting marathon: how CD8+ T cells fine‐tune metabolic fitness. Immunology & Cell Biology, 100(2), 83-86.
Schulz, Anna M. & Zehn, Dietmar
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Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T cell development. Nature Immunology, 24(3), 501-515.
Scherer, Stefanie; Oberle, Susanne G.; Kanev, Kristiyan; Gerullis, Ann-Katrin; Wu, Ming; de Almeida, Gustavo P.; Puleston, Daniel J.; Baixauli, Francesc; Aly, Lilian; Greco, Alessandro; Nizharadze, Tamar; Becker, Nils B.; Hoesslin, Madlaina v.; Donhauser, Lara V.; Berner, Jacqueline; Chu, Talyn; McNamara, Hayley A.; Esencan, Zeynep; Roelli, Patrick ... & Zehn, Dietmar
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Tapping the keg of discovery to advance T cell therapy. Nature Immunology, 24(2), 213-215.
Schulz, Anna M.; Zebley, Caitlin C.; Youngblood, Ben & Zehn, Dietmar
