Constitutive Glycolytic Metabolism Supports CD8+T Cell Effector Memory Differentiation during Viral Infection.
Extensive metabolic changes accompany T cell activation, including a switch to glycolytic energy production and increased biosynthesis. Recent studies suggest that subsequent return to reliance on oxidative phosphorylation and increasing spare respiratory capacity are essential for the differentiation of memory CD8+T cells. In contrast, we found that constitutive glycolytic metabolism and suppression of oxidative phosphorylation in CD8+T cells, achieved by conditional deletion of hypoxia-inducible factor regulator Vhl, accelerated CD8+memory cell differentiation during viral infection. Despite sustained glycolysis, CD8+memory cells emerged that upregulated key memory-associated cytokine receptors and transcription factors and showed a heightened response to secondary challenge. In addition, increased glycolysis not only permitted memory formation, but it also favored the formation of long-lived effector-memory CD8+T cells. These data redefine the role of cellular metabolism in memory cell differentiation, showing that reliance on glycolytic metabolism does not hinder formation of a protective memory population.
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Anthony T
AT
Phan
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Andrew L
AL
Doedens
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2, UK.
Asis
A
Palazon
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2, UK.
Petros A
PA
Tyrakis
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Kitty P
KP
Cheung
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2, UK; Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.
Randall S
RS
Johnson
Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: agoldrath@ucsd.edu.
Ananda W
AW
Goldrath
D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006019:Glycolysis / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus; D051379:Mice; D008822:Mice, Transgenic; D010085:Oxidative Phosphorylation