Metabolomic profiling reveals the potential of fatty acids as regulators of exhausted CD8 T cells during chronic viral infection

Chronic infections induce CD8 T cell exhaustion, marked by impaired effector function. While intrinsic drivers are well studied, the role of the surrounding metabolic environment in shaping exhausted CD8 T cells (Tex) is less understood. Using untargeted metabolomics and the murine lymphocytic choriomeningitis virus infection model, we investigated systemic metabolite changes following acute vs. chronic viral infections. We identified distinct short-term and persistent metabolite shifts, with the most significant differences occurring transiently during the early phase of the sustained infection. This included nutrient changes that were partially associated with CD8 T cell-induced anorexia and lipolysis. One remarkable observation was the elevation of medium- and long-chain fatty acids (FA) and acylcarnitines during the first week after chronic infection. Consistently, virus-specific CD8 T cells from chronic infection exhibited increased lipid accumulation and uptake compared to their counterparts from acute infection, particularly the stem-like Tex (Tex^STEM), which generates Tex^INT that directly limit viral replication. Notably, only Tex^STEM increased oxidative metabolism upon ex vivo FA exposure, while short-term administration of FA during late chronic infection exclusively increased Tex^STEM and their mitochondrial potential. The last-mentioned treatment also led to reduced Tex^INT and enhanced PD-1 across all Tex subsets, which coincided with compromised viral control. Our study offers a valuable resource for investigating the regulatory role of specific metabolites during acute and chronic viral infections and highlights the potential of FA to fine-tune Tex subsets during protracted infections.