REPROGRAMIT · Control of T cell differentiation and plasticity through mitochondrial reprogramming
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-08-01 → 2021-07-31
- EU contribution
- €171,461
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Control of T cell differentiation and plasticity through mitochondrial reprogramming
This project aimed at understanding whether mitochondrial morphology and function regulate the transcriptional and epigenetic landscape of the distinct T cell subsets. The combination of pharmacologic and genetic approaches in in vitro and in vivo models of T cell differentiation and inflammation, revealed a role for mitochondrial membrane organization and metabolism in sustaining the effector function of Th17 cells. Genetic targeting of the proteins involved in the fusion or fission of mitochondrial membranes (mitochondrial dynamics) using in vitro and in in vivo models of disease, together with immune and metabolic assays, let me to identify and characterize the role of the mitochondrial profusion protein OPA1 in Th17 effector function. During the course of this project, I found that deletion of OPA1 in T cells promotes profound metabolic, transcriptional and proteomic alterations which restrain Th17 pathogenicity, while keeping intact the effector function across other T cell subsets (i.e. Th1, Th2 or regulatory T cells, Tregs). These findings highlight the requirement of mitochondrial function in Th17 cells and reveal novel metabolic vulnerabilities of Th17 cells that can be exploited therapeutically in Th17-cell related pathologies.
Data: CORDIS, © European Union
Project objective
Mitochondria participate during the metabolic reprogramming of naive T cells. However, the molecular mechanisms by which mitochondria regulate T cell differentiation remain elusive. The project aims at revealing the mechanisms behind mitochondrial function and lineage specification and maintenance. Combining high-throughput analysis of gene expression and chromatin epigenetic status with biochemical, metabolic, cellular, and in vivo and in vitro approaches, we want to assess how mitochondria coordinate the metabolic status of the cell to transcriptional and epigenetic changes to control T cell differentiation and function in distinct inflammatory environments. For that our challenges are; (Obj.1) To investigate the role of mitochondrial dynamics in the metabolic reprogramming of T cell differentiation, (Obj.2) To study how metabolic pathways shape the transcriptional and epigenetic networks of the T cell lineages, (Obj.3) To identify mitochondria-to-nucleus signaling pathways that regulate T cell differentiation through modification of the transcriptional and epigenetic landscape, and (Obj.4) To investigate the therapeutic potential of reprogramming mitochondrial function in T cell responses against infection and cancer. REPROGRAMMIT will unveil significant breakthrough on (1) how mitochondria regulate the metabolic profiles of the distinct T cell subsets, (2) the identification of molecular candidates that reverse or modify T cell transcriptional programs through regulation of mitochondrial function, (3) the understanding on how nutrient availability and metabolic intermediates shape T cell differentiation and plasticity. In sum, REPROGRAMIT puts forward an ambitious and multidisciplinary but feasible program with the wide purpose of identifying novel checkpoints based on the crosstalk between mitochondria and the epigenome, with the final goal to modulate T cell immune responses against infection and cancer by reprogramming mitochondrial function.
Original text from CORDIS.
Participants
- MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV · MUNCHENCoordinatorGermany
Links
Data: CORDIS, © European Union