Purine nucleobases enhance CD8+ T cell effector function

Abstract

During antiviral immune responses, activated immune cells remodel metabolic pathways towards uptake and utilization of biosynthetic and bioenergetic metabolites. Concurrently, viral infections alter metabolic environments, impacting metabolite availability for the establishment of an effective immune response. Here, we integrated in vivo metabolomics data from murine and human viral infections with in vitro metabolite screens, identifying purine nucleobases as novel immunometabolites that enhance CD8+ T cell effector function. We found that CD8+ T cells can switch from resource-intensive purine de novo synthesis to purine salvage pathway, to produce nucleotides from purine nucleobases. This strategy of metabolic adaptation allows diversion of biosynthetic and bioenergetic resources towards enhancing effector molecule production. Our findings unveil an adaptation strategy by CD8+ T cells to manage metabolic challenges in dynamic organismal environments and suggest pharmacological targets in purine metabolism as potential targets for immunotherapy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/669899v1_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@17b4b15org.highwire.dtl.DTLVardef@17e57a3org.highwire.dtl.DTLVardef@1abc36aorg.highwire.dtl.DTLVardef@1aa704a_HPS_FORMAT_FIGEXP M_FIG C_FIG Instead of producing nucleotides via purine de novo synthesis, CD8+ T cells can import and utilize purine nucleobases via the purine salvage pathway to divert bioenergetic and biosynthetic resources towards effector function. By shifting from purine de novo synthesis to the purine salvage pathway, cells save significant resources: 5 moles of the key bioenergetic metabolite ATP, and biosynthetic metabolites including 2 moles of glutamine, 1 mole each of serine or glycine, and 1 mole of aspartate.