Abstract
Memory CD8 T cells can provide long-term protection against tumors, which depends on their enhanced proliferative capacity, self-renewal and unique metabolic rewiring to sustain cellular fitness. Specifically, memory CD8 T cells engage oxidative phosphorylation and fatty acid oxidation to fulfill their metabolic demands. In contrast, tumor-infiltrating lymphocytes (TILs) display severe metabolic defects, which may underlie their functional decline. Here, we show that overexpression of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the master regulator of mitochondrial biogenesis (MB), favors CD8 T cell central memory formation rather than resident memory generation. PGC-1α-overexpressing CD8 T cells persist and mediate more robust recall responses to bacterial infection or peptide vaccination. Importantly, CD8 T cells with enhanced PGC-1α expression provide stronger antitumor immunity in a mouse melanoma model. Moreover, TILs overexpressing PGC-1α maintain higher mitochondrial activity and improved expansion when rechallenged in a tumor-free host. Altogether, our findings indicate that enforcing mitochondrial biogenesis promotes CD8 T cell memory formation, metabolic fitness, and antitumor immunity in vivo.
Highlights
Enforced PGC-1α expression promotes CD8 T cell persistence, memory formation, and antigen recall potential Recent studies from our group and others showed that the deficiency of Rictor, the core component of mammalian target of rapamycin complex 2, favors CD8 T cell memory
PGC-1α is well characterized in various organs, such as the heart, skeletal muscle, or liver, its expression pattern and functionality in CD8 T cells remain elusive
The mRNA level of PGC-1α in CD8 T cells is decreased at 24, 48, and 72 h post activation compared to naive T cells, and PGC-1β expression is comparable between naive and 24 h post activation, which is downregulated at the other time points tested (Supplementary Fig. 1b, c)
Summary
CD8 T cells mount protective responses against viral/bacterial infections and cancers.[1,2] The infiltration of cytotoxic CD8 T cells into tumors and their long-term persistence in vivo are positively correlated with an improvement in the disease-free survival of cancer patients.[3,4,5] Memory CD8 T cells are characterized by the expression of CD62L and CD127, which allow their trafficking into lymphoid tissues and enhanced survival capacity, respectively.[6,7]Metabolically, memory CD8 T cells display a considerable spare respiratory capacity (SRC), which is largely driven by fatty acid oxidation (FAO) compared to naive T cells having lower levels of oxidative phosphorylation (OXPHOS) or effector CD8 T cells, which favor glycolysis to support their effector function.[8]. A unique feature of memory T cells is their ability to mediate more rapid recall responses at a higher magnitude upon antigen rechallenge.[9,10] Of note, CD8 memory T cells have more mitochondrial mass than their naive counterparts, supporting a metabolic phenotype that empowers memory T cells with superior metabolic fitness, including both increased OXPHOS and glycolytic capacity.[11]
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