Abstract
An effective adaptive immune response requires rapid T cell proliferation, followed by equally robust cell death. These two processes are coordinately regulated to allow sufficient magnitude of response followed by its rapid resolution, while also providing the maintenance of T cell memory. Both aspects of this T cell response are characterized by profound changes in metabolism; glycolysis drives proliferation whereas oxidative phosphorylation supports the survival of memory T cells. While much is known about the separate aspects of T cell expansion and contraction, considerably less is understood regarding how these processes might be connected. We report a link between the induction of glycolysis in CD8+ T cells and upregulation of the inhibitor of complex I and oxidative phosphorylation, methylation-controlled J protein (MCJ). MCJ acts synergistically with glycolysis to promote caspase-3 activity. Effector CD8+ T cells from MCJ-deficient mice manifest reduced glycolysis and considerably less active caspase-3 compared to wild-type cells. Consistent with these observations, in non-glycolytic CD8+ T cells cultured in the presence of IL-15, MCJ expression is repressed by methylation, which parallels their reduced active caspase-3 and increased survival compared to glycolytic IL-2-cultured T cells. Elevated levels of MCJ are also observed in vivo in the highly proliferative and glycolytic subset of CD4-CD8- T cells in Fas-deficient lpr mice. This subset also manifests elevated levels of activated caspase-3 and rapid cell death. Collectively, these data demonstrate tight linkage of glycolysis, MCJ expression, and active caspase-3 that serves to prevent the accumulation and promote the timely death of highly proliferative CD8+ T cells.
Highlights
The adaptive immune response is characterized by rapid proliferation of responding T cells followed by rapid cell death
IL-2-cultured activated CD8+ T cells manifested a rapid increase in glycolysis, as measured by extracellular acidification rate (ECAR) and a low oxygen consumption rate (OCR) on day 6, whereas IL-15-cultured CD8+ T cells had the opposite metabolic profile, consistent with oxidative phosphorylation, in agreement with previous reports
As oxygen consumption is primarily due to mitochondrial activity of the electron transport chain (ETC), we examined complex I activity in naïve versus IL-2-cultured CD8+ T cells
Summary
The adaptive immune response is characterized by rapid proliferation of responding T cells followed by rapid cell death These two processes need to be tightly coordinated, lest this result in excessive expansion or loss of T cells. Whereas much is known about the metabolic shifts leading to T cell proliferation and the death pathways resulting in contraction, less is appreciated about the possible close linkage of these two processes Understanding this connection is critical to MCJ Links Proliferation and Death the design of T cell immunotherapy where enormous expansion of T cells is performed ex vivo using exogenous cytokines followed by the need for the cells to survive in vivo when infused in patients (Hollyman et al, 2009; Tumaini et al, 2013; Geyer et al, 2018). IL-15 reduces glycolysis and promotes oxidative phosphorylation and T cell survival to the memory stage, the mechanism of survival is not clear (van der Windt et al, 2012; Saligrama et al, 2014)
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