Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling

By Laura A. Sena, Sha Li, Amit Jairaman, M. Prakriya, Teresa Ezponda, David A Hildeman, Chyung-Ru Wang, P. Schumacker, J. Licht, H. Perlman and 2 more. Immunity, 2013

1,230 citations recorded by the source corpus.

SUMMARY It is widely appreciated that T cells increase glycolytic flux during activation, however the role of mitochondrial flux is unclear. Here we have shown that mitochondrial metabolism, in the absence of glucose metabolism, was 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, however 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 production of complex III ROS.

Subfields: Immunology, Neurology

View Paper: https://www.semanticscholar.org/paper/7a214bc7522b60abf0b9ddc9548361e0e903cd03

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Citations in the corpus

Memory CD8+ T cells use cell intrinsic lipolysis to support the metabolic programming necessary for development (2014, background): “Although Teff cells can engage OXPHOS (Chang et al., 2013; Wang et al., 2011), which is neces- sary for their Ag driven proliferation (Sena et al., 2013), memory T cells rely on this metabolic pathway, and in particular, the use of fatty acids (FA) to fuel this process (Pearce et al., 2013).”
Normalization of CD4+ T Cell Metabolism Reverses Lupus (2015, background): “More recently, the field has gained a better appreciation for mitochondrial oxidativemetabolism inmediating T cell activation and proliferation (12, 14, 23).”
Metabolic Regulation of Immune Responses (2014, background): “By disrupting the Uqcrfs gene, a critical component of complex III, the authors’ generated mice in which mROS was specifically reduced in CD4+ T cells (102).”
Metabolic Instruction of Immunity (2017, neutral): “However, activation initiated by TCR ligation and binding with costimulatory molecules also augments OXPHOS in T cells (Chang et al., 2013; Sena et al., 2013).”
Mitochondria in the regulation of innate and adaptive immunity (2015, neutral): “However, glycolysis but not mitochondrial metabolism is dispensable for T cell activation and production of the cytokine IL-2 prior to proliferation (Sena et al., 2013) (Figure 4).”
T cell lipid peroxidation induces ferroptosis and prevents immunity to infection (2015, background): “Recently, T cell activation, expansion, and effector function have been shown to involve ROS as an important signaling molecule (Wang and Green, 2012; Pearce and Pearce, 2013; Sena et al., 2013).”
The Glucose Transporter Glut1 is Selectively Essential for CD4 T Cell Activation and Effector Function (2014, neutral): “In vivo, T cells require mitochondrial ROS (Sena et al., 2013), lipid synthesis (Kidani et al., 2013), and amino acid uptake (Sinclair et al., 2013).”
Repurposing mitochondria from ATP production to ROS generation drives a pro-inflammatory phenotype in macrophages that depends on succinate oxidation by complex II (2016, background): “On the other hand, activated T cells maintain oxidative phosphorylation in conjunction with glycolysis, but whether oxidative metabolism is required for the production of biosynthetic precursors and ATP following stimulation or to generate a ROS signal is unclear (Sena et al., 2013).”
Mitochondrial reactive oxygen species and cancer (2014, background): “For example, the immune system, an important modulator of cancer growth, has been shown to be sensitive to ROS levels [99].”