PIM1 kinase-regulated cellular metabolism sustains differentiation and function of effector CD8+ T cells during...

CD8+ T-cell differentiation during chronic viral infection is supported by metabolic reprogramming to meet distinct bioenergetic demands. Early effector CD8+ T-cell differentiation and function are supported by the PI3K-Akt-mTOR pathway, while the differentiation of late exhausted CD8+ T cells remains incompletely understood. We first characterized the metabolic heterogeneity of the progenitor, effector, and exhausted CD8+ T-cell subsets in chronic infection by utilizing the Compass algorithm, which provides metabolic state predictions based on single-cell RNA sequencing data and flux-based analysis. Our analysis revealed metabolic programs distinct to each subset of virus-specific CD8+ T cells. In addition, it is known that the differentiation of progenitor to effector CD8+ T cells depends on IL-21-producing CD4+ T cells. We found that PIM1 kinase, a known regulator of cellular energy metabolism that functions downstream of IL-21 signaling, displays high gene expression in the effector CD8 T-cell subset. Using the lymphocytic choriomeningitis virus clone 13 model of chronic viral infection, we showed that CD8+ T cell-specific deletion of PIM1 kinase impairs the differentiation and cytolytic function of late effector CD8+ T cells. Furthermore, deficiency in PIM1 kinase reduced oxidative and glycolytic metabolism, potentially contributing to the diminished effector differentiation and function. Overall, these data reveal not only the metabolic heterogeneity of exhausted CD8+ T cells, but also how metabolic regulation through the IL-21-PIM1 axis impacts CD8+ T-cell differentiation.