Mitochondrial Respiratory Capacity Is a Critical Regulator of CD8+ T Cell Memory Development

• Published in: Immunity (Cambridge, Mass.) Vol. 36; no. 1; pp. 68 - 78
• Main Authors: van der Windt, Gerritje J.W., Everts, Bart, Chang, Chih-Hao, Curtis, Jonathan D., Freitas, Tori C., Amiel, Eyal, Pearce, Edward J., Pearce, Erika L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.01.2012; Elsevier Limited
• Subjects: Acidification; Animals; Bioenergetics; Carnitine O-Palmitoyltransferase - metabolism; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - enzymology; CD8-Positive T-Lymphocytes - immunology; Cell Respiration - physiology; Cytokines; Fatty Acids - metabolism; Flow Cytometry; Glucose; Immunologic Memory; Infections; Interleukin-15 - metabolism; Metabolism; Mice; Mice, Inbred C57BL; Mitochondria - enzymology; Mitochondria - metabolism; Models, Biological; Oxidation-Reduction; Real-Time Polymerase Chain Reaction; Rodents; Survival analysis
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2011.12.007

CD8+ T cells undergo major metabolic changes upon activation, but how metabolism influences the establishment of long-lived memory T cells after infection remains a key question. We have shown here that CD8+ memory T cells, but not CD8+ T effector (Teff) cells, possessed substantial mitochondrial spare respiratory capacity (SRC). SRC is the extra capacity available in cells to produce energy in response to increased stress or work and as such is associated with cellular survival. We found that interleukin-15 (IL-15), a cytokine critical for CD8+ memory T cells, regulated SRC and oxidative metabolism by promoting mitochondrial biogenesis and expression of carnitine palmitoyl transferase (CPT1a), a metabolic enzyme that controls the rate-limiting step to mitochondrial fatty acid oxidation (FAO). These results show how cytokines control the bioenergetic stability of memory T cells after infection by regulating mitochondrial metabolism. ► CD8+ memory T cells possess substantial mitochondrial spare respiratory capacity (SRC) ► IL-15 regulates SRC by promoting mitochondrial biogenesis and CPT1a expression ► SRC in CD8+ memory T cells is dependent on mitochondrial fatty acid oxidation (FAO) ► Mitochondrial FAO enhances T cell survival and promotes CD8+ memory T cell development