Mitochondria Are Required for Antigen-Specific T Cell Activation through Reactive Oxygen Species Signaling

• Published in: Immunity (Cambridge, Mass.) Vol. 38; no. 2; pp. 225 - 236
• Main Authors: Sena, Laura A., Li, Sha, Jairaman, Amit, Prakriya, Murali, Ezponda, Teresa, Hildeman, David A., Wang, Chyung-Ru, Schumacker, Paul T., Licht, Jonathan D., Perlman, Harris, Bryce, Paul J., Chandel, Navdeep S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.02.2013; Elsevier Limited
• Subjects: Animals; Apoptosis; Biosynthesis; Cell growth; Cell Proliferation; Electron Transport Complex III - metabolism; Female; Flow cytometry; Gene Expression; Homeodomain Proteins - genetics; Homeodomain Proteins - immunology; Immune system; Infections; Interleukin-2 - biosynthesis; Interleukin-2 - immunology; Iron-Sulfur Proteins - deficiency; Iron-Sulfur Proteins - genetics; Laboratories; Lymphatic system; Lymphocyte Activation; Lymphopenia - immunology; Lymphopenia - metabolism; Metabolism; Metabolites; Mice; Mice, Knockout; Mitochondria; Mitochondria - genetics; Mitochondria - immunology; Mitochondria - metabolism; NFATC Transcription Factors - genetics; NFATC Transcription Factors - immunology; Oxygen; Reactive Oxygen Species - metabolism; Signal Transduction; T cell receptors; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Transcription factors; Tumor Necrosis Factor Receptor Superfamily, Member 7 - genetics; Tumor Necrosis Factor Receptor Superfamily, Member 7 - immunology
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2012.10.020

It is widely appreciated that T cells increase glycolytic flux during activation, but the role of mitochondrial flux is unclear. Here, we have shown that mitochondrial metabolism in the absence of glucose metabolism is sufficient to support interleukin-2 (IL-2) induction. Furthermore, we used mice with reduced mitochondrial reactive oxygen species (mROS) production in T cells (T-Uqcrfs−/− mice) to show that mitochondria are required for T cell activation to produce mROS for activation of nuclear factor of activated T cells (NFAT) and subsequent IL-2 induction. These mice could not induce antigen-specific expansion of T cells in vivo, but Uqcrfs1−/− T cells retained the ability to proliferate in vivo under lymphopenic conditions. This suggests that Uqcrfs1−/− T cells were not lacking bioenergetically but rather lacked specific ROS-dependent signaling events needed for antigen-specific expansion. Thus, mitochondrial metabolism is a critical component of T cell activation through the production of complex III ROS. ▸ Mitochondrial metabolism is sufficient to support T cell activation in vitro ▸ Mitochondrial ROS are induced by TCR-initiated calcium influx ▸ Mitochondrial complex III ROS are required for NFAT activation and IL-2 induction ▸ Induction of mitochondrial ROS is required for antigen-specific T cell responses in vivo