Oxphos, not Glycolysis, Promotes the Survival Of Effector Tc17 Cells 2307301

Abstract

Abstract Introduction IL-17A+ T cells are implicated in immunity and immunopathology. Fungal infections primarily occur in immunocompromised hosts. We have previously shown that experimental fungal vaccine-induced Tc17 cells are stable, durable, and necessary for sterilizing immunity in CD4+ T cell deficiency. Metabolism is pliable but integral for T cell homeostasis. T cell expansion involves metabolic shift from OXPHOS to glycolysis to meet rapid energy needs, but Tc17 cell metabolic adaptations that portend longevity are poorly defined. Methods We used a mouse model of fungal vaccination to evaluate metabolic adaptations of Tc17 cells in draining lymph nodes by flow cytometry. 2-DG, oligomycin, sodium oxamate, and sodium bicarbonate were used to inhibit glucose uptake, OXPHOS, lactate production, and lactate-induced extracellular acidification neutralization, respectively. Results Effector Tc17 cells were metabolically highly active with higher proliferation and translation than IFN+ CD8+ T (Tc1) cells. Glucose was necessary for Tc17 cell expansion, but with reduced dependency in late expansion despite the higher metabolism. Tc17 cells preferentially channeled glucose to OXPHOS rather than glycolysis, correlated with their higher mitochondrial mass and function. Consistent with this, RNASeq data showed that Tc17 cells, unlike Tc1 cells, showed higher expression of TCA cycle and OXPHOS-related transcripts and low PDHK1 expression, despite a higher glycolysis signature. As glycolysis exuded lactate acidifies the extracellular environment, neutralizing acidification enhanced Tc1 cells, but not Tc17 cells. Similarly, inhibiting lactate production preferentially rescued Tc1 cells. Conclusion The effector Tc17 cells prudently channel the glucose to OXPHOS metabolism over glycolysis meet high energy demand. In contrast, glycolysis-dependent Tc1 cells showed poor survival but countered by inhibition of lactate production. Collectively, effector Tc17 cells are programmed for longevity by adopting OXPHOS than glycolysis. Funding Source NIH-NIAID R01153522 (to SGN) Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)