GSK3b and dsRNA in CD8 cells

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PROJECT SUMMARY Double-stranded RNA (dsRNA) is a well-known pathogen-associated molecular pattern (PAMP) generated during viral infections that triggers the innate immune response and plays a critical role in virus protection through the direct effect on type I IFN. However, in recent years it has been clear that this pathway can also be induced by endogenous dsRNA, with mitochondria transcripts being one of the major sources of endogenous dsRNA. The presence of endogenous dsRNA suggests that there must be mechanisms in place to keep on check their accumulation to avoid triggering RLRs pathways. Although there is a number of studies on how the production of type I IFN resulting from endogenous dsRNA can indirectly modulate T cell response, no previous studies have examined dsRNA in T cells. Our recent studies have revealed the presence of endogenous dsRNA in CD8 cells upon activation, and mitochondria seems to be the primary source. In addition, we identify a new mechanism that CD8 cells use to restrict the levels of dsRNA generated: inactivation of mitochondria GSK3 by phosphorylation on Ser389. Interestingly, failure to inactivate GSK3 by phospho-Ser389 results in a greater accumulation of mitochondrial dsRNA in activated CD8 cells. Importantly, we also found that failure to inactivate GSK3 by phospho-Ser389 results in higher levels of IFN produced by CD8 cells. We hypothesize that mitochondrial dsRNAs are generated during activation of CD8 cells, can trigger the RLR pathway and contribute to sustain IFN production. We also propose that mitochondrial GSK3 interferes with the mitochondrial degradosome and that inactivation of mitochondrial GSK3 through phosphorylation on Ser389 in response to dsRNA is essential for maintaining dsRNA-homeostasis and restricting IFN production. We will test this hypothesis with the following specific aims: 1) to show that mitochondrial dsRNA is generated during activation of CD8 cells and contributes to the production of IFN. 2) to show that inactivation of GSK3 through Ser389- phosphorylation plays a role in the homeostasis of mitochondrial dsRNA during activation of CD8 cells. The results from the proposed studies could be a major breakthrough since they will show how endogenous dsRNA can contribute to sustain cytokine production in activated CD8 cells, and its potential impact on autoimmune disease.