Magnitude of STING Signaling Determines CD8 T cell Memory
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Memory CD8+ T cells are critical for long-term protection against intracellular pathogens and tumors. STING signals enable the transcription of pro-inflammatory molecules, such as type I IFNs, in response to nucleic acids from pathogens or self . Although the STING signaling pathway is best characterized for generating antiviral responses, recent evidence indicates STING signaling is involved in regulating IFN- independent cellular responses in innate immune cells. However, it's role in T cells is still poorly understood. Our collaborators published that enhanced STING signaling leads to a decrease in T cell protective immunity in a mechanism independent of direct IFN signaling on T cells. Our data indicates that CD8 T cells expand and clear infection but subsequently vanish without differentiating into memory. This is not due to impairments in memory programming, rather, CD8 T cell death is induced due to high levels of the apoptotic molecule Bim. Our data also suggest that T cell death via STING signaling could be attributed to its ability to modulate tryptophan metabolism. STING signaling can upregulate the enzyme IDO to catalyze the oxidation of tryptophan, a necessary amino acid for T cell survival. Indeed, IDO inhibition is able to return Bim expression to wildtype levels and restore the generation of memory T cells. Collectively, our data emphasizes a role for tryptophan metabolism in the generation of memory CD8 T cells and suggests enhancing STING signaling might not be beneficial in all T cell responses.
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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License.