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Periodic Report Summary 1 - MITOCHONDRIA (Unraveling and targeting mitochondrial biogenesis in CD8+ T cells to improve memory formation and vaccine efficacy)

The overall objective of the proposed research is to determine and target the mechanism that underlies the promotion of mitochondrial biogenesis (MB) during CD8+ memory T cell (Tm) formation. I hypothesized that: (1) PGC-1 is critical for the generation of long-lived CD8+ Tm cells, and (2) that pharmacological agents that induce MB can promote CD8+ Tm cell formation and function. I have developed two specific objectives to address these hypotheses:
1) Determine the role of PGC-1 in mitochondrial metabolism during CD8+ Tm development.
2) Investigate whether agents that promote MB enhance vaccine efficacy.

Regarding hypothesis 1, we found no indication that PGC1a deficient CD8 T cells have impaired MB or spare respiratory capacity (SRC). For PGC1b the results were mixed and additional repeats would be required for firm conclusions. We have also performed several Seahorse experiments (real-time activation by PMA/ionomycin) for both PGC1a and PGC1b deficient CD8 T cells, and found no consistent differences. In addition, we have performed in vivo experiments for PGC1a and PGC1b deficient CD8 cells. We found similar Tm development or recall responses of PGC1a or PGC1b deficient CD8 T cells. Taken together, so far I can conclude that either PGC1 is not essential for CD8 Tm metabolism and development, or, that PGC1a and PGC1b can compensate for each other’s absence. A PGC1 double deficient T cell will be required to provide a definite answer to this question.

To test hypothesis 2, we have tested several drugs on both murine and human T cells, including resveratrol, nicotinamide mononucleotide (NMN) and rosiglitazone. We found that resveratrol and NMN can induce MB and SRC in murine CD8 T cells. We are in the progress of testing these (and other) drugs on human T cells. We have also performed experiments using resveratrol in vivo, and have not found an effect yet. We will attempt to optimize our system to fully ensure that resveratrol has no effect on Tm development and persistence. Together, we can conclude for objective 2 that in vitro resveratrol and NMN are able to induce MB and SRC in murine T cells, and these drugs may be promising to improve vaccination efficacy in vivo.

Reported by

Academisch Medisch Centrum bij de Universiteit van Amsterdam


Life Sciences
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