Elevation of systemic lipids during persistent viral infection modulates a stem-like population of exhausted T cells and leads to enhanced viral clearance

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B175
Abstract ID: 6015

Presenting Author:
Katelynn R Kazane , Graduate Student at UCSD

Abstract:

Immune adaptations upon persistent viral infection are necessary to balance viral control and immunopathology. While these changes have been well studied, crosstalk between immune and non-immune systems remains to be explored. Using lymphocytic choriomeningitis virus in mice and untargeted metabolomics, we uncovered a systemic nutritional shift that involved elevation of medium and long chain fatty acids (FA) upon infection with a persistent (but not acute) viral isolate. This FA elevation resulted from CD8-T cell-driven adipose tissue lipolysis and was limited to the first week of infection. Concurrently, stem-like exhausted CD8 T cells (Tex^STEM) which emerge early after infection and are essential for long-term viral control, showed an increased capacity for FA uptake, elevated neutral lipid content and enhanced FA oxidation. Using this information, we treated persistently infected mice during the chronic phase of infection, when endogenous FAs are no longer elevated, with a mix of medium and long chain FA. This treatment resulted in an increase in Tex^STEM cells and their mitochondrial fitness. Importantly, this treatment also led to enhanced viral control. Together, these data reveal a previously unknown crosstalk between Tex cells and systemic metabolism, which leads to changes in nutrient availability early after infection, and show that manipulating metabolites after establishment of a chronic infection can benefit Tex^STEM cells and improve viral control.