The role of mitophagy during memory CD8+ T cells formation
Details
![Ressource 1](https://serval.unil.ch/static/img/forbidden.png)
UNIL restricted access
State: Public
Version: After imprimatur
License: Not specified
Serval ID
serval:BIB_DD7703438DA5
Type
A Master's thesis.
Publication sub-type
Master (thesis) (master)
Collection
Publications
Institution
Title
The role of mitophagy during memory CD8+ T cells formation
Director(s)
HO P.-C.
Codirector(s)
FRANCO F.
Institution details
Université de Lausanne, Faculté de biologie et médecine
Publication state
Accepted
Issued date
2022
Language
english
Number of pages
30
Abstract
The formation and persistence of memory CD8+ T cells is a core feature of the immune system to maintain long-term protection against intracellular pathogens. To reach this state of differentiation, the naïve CD8+ T cell will be activated and undergoes numerous reshaping, including changes in its metabolism. Memory CD8+ T cells switch to OXPHOS supported by lipid metabolism to provide the energy required for the cell's proper functioning and long-term survival. Moreover, mitochondria of memory CD8+ T cells have the particularity to offer spare respiratory capacity (SRC), which supplies backup energy needed for eventual reactivation. Thus, the mitochondria orchestrate to a large extent the metabolism of the memory CD8+ T cells by supplying OXPHOS, lipid metabolism, and by providing SRC. It is therefore expected that their quality must be tightly regulated. The process by which damaged mitochondria are degraded is called mitophagy. Mitophagy is a type of autophagy that specifically targets mitochondria. Interestingly, a recent study has shown that autophagy is essential for the formation of immune memory cells. Moreover, the previous experiments in this laboratory have suggested that CD8+ T cells increase their mitophagy rate during memory cell differentiation. In addition, the deletion of Nix, a key gene for the mitophagy process, hindered memory formation, through the loss of NIX KO CD8+ T cells from day 15 post-LCMV Armstrong infection. The loss of NIX KO CD8+ T cells could potentially be explained by the accumulation of large amounts of mROS observed in these cells during the contraction phase. Thus, mitophagy appears to be crucial for memory CD8+ T cell formation and maintenance. However, it remains unknown what signals trigger the mitophagy process, and the mechanism by which mROS leads to cell loss needs to be further investigated.
Here, we have seen that in-vitro, the upregulation of mitophagy during the development of memory cells is triggered by IL15 signaling, notably by promoting the expression of key mitophagy genes. In addition, to further investigate the impact of mROS in the NIX KO CD8+ T cells, we tried to bypass the accumulation of mROS by inducing the expression of antioxidant genes through the NRF2 pathway. We designed two retroviral vectors that constitutively overexpress NRF2, by deleting its NEH2 regulatory domain. Those vectors could be used to induce the antioxidant genes (ARE genes) in CD8+ T cells.
Our results suggest that the induction of the mitophagy process by IL15 signaling appears to be involved in the formation of memory CD8+ T cells in mice. A better understanding of what governs the formation of immune memory offers insights into the discovery of new therapies, particularly in the context of vaccine effectiveness.
Here, we have seen that in-vitro, the upregulation of mitophagy during the development of memory cells is triggered by IL15 signaling, notably by promoting the expression of key mitophagy genes. In addition, to further investigate the impact of mROS in the NIX KO CD8+ T cells, we tried to bypass the accumulation of mROS by inducing the expression of antioxidant genes through the NRF2 pathway. We designed two retroviral vectors that constitutively overexpress NRF2, by deleting its NEH2 regulatory domain. Those vectors could be used to induce the antioxidant genes (ARE genes) in CD8+ T cells.
Our results suggest that the induction of the mitophagy process by IL15 signaling appears to be involved in the formation of memory CD8+ T cells in mice. A better understanding of what governs the formation of immune memory offers insights into the discovery of new therapies, particularly in the context of vaccine effectiveness.
Keywords
Memory CD8+ T cells, metabolic reprogramming, mitochondria, mitophagy, mROS
Create date
11/09/2023 15:40
Last modification date
24/07/2024 6:59