PPARß/d-orchestrated metabolic reprogramming supports the formation and maintenance of memory CD8+ T cells [scRNA-seq]

The formation of antigen-specific memory CD8+ T cells is one of the most important features of the adaptative immune system, allowing the establishment of long-term protection against secondary infections. Although emerging evidence suggests that metabolic reprogramming is crucial for memory T cell differentiation and survival, the underlying mechanisms that drive metabolic rewiring needed for memory T cells remain unclear. Here, we found that the nuclear receptor peroxisome proliferator-activated receptor-beta/delta (PPARß/d) was upregulated to instruct the metabolic reprogramming, including downregulation of aerobic glycolysis and the promotion of oxidative metabolism and fatty acid oxidation, that occurs during the transition toward the establishment of central memory CD8+ T cells. Mechanistically, the exposure to interleukin-15 (IL-15) and expression of T cell factor 1 (TCF1) could coordinately activated the PPARß/d pathway during acute viral infection and chronic antigen exposure contexts, counteracting apoptosis induced by antigen clearance and metabolic stress. Together, our work indicates that PPARß/d is a master metabolic regulator orchestrating the metabolic reprogramming required for the establishment of a metabolic profile favorable for T cells longevity. Overall design: 10K P14 WT and PPARb deficient CD8+ T cells were transferred in B6 host which were infected the next next with LCMV Armstrong. Transferred P14 CD8+ T cells were sorted from spleens at d15 after Arm infection and prepared and then sequenced using the Chromium Next GEM Single Cell 3' kit from 10x Genomics