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

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.

doi:10.1016/j.immuni.2012.10.020

Cited by 1,042 publications

(1,069 citation statements)

References 48 publications

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“…During T cell activation, ROS derived from mitochondrial complex III critically underpin IL-2 production and proliferation (29). Furthermore, activated T cells from individuals with rheumatoid arthritis demonstrate reduced abundance of ROS, associated with increased apoptosis, which could be recapitulated in healthy cells by scavenging mROS (30).…”

Section: Discussionmentioning

confidence: 99%

The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions

Dimeloe

Mehling

Frick

et al. 2016

The Journal of Immunology

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Effector memory (EM) CD4+ T cells recirculate between normoxic blood and hypoxic tissues to screen for cognate Ag. How mitochondria of these cells, shuttling between normoxia and hypoxia, maintain bioenergetic efficiency and stably uphold antiapoptotic features is unknown. In this study, we found that human EM CD4+ T cells had greater spare respiratory capacity (SRC) than did naive counterparts, which was immediately accessed under hypoxia. Consequently, hypoxic EM cells maintained ATP levels, survived and migrated better than did hypoxic naive cells, and hypoxia did not impair their capacity to produce IFN-γ. EM CD4+ T cells also had more abundant cytosolic GAPDH and increased glycolytic reserve. In contrast to SRC, glycolytic reserve was not tapped under hypoxic conditions, and, under hypoxia, glucose metabolism contributed similarly to ATP production in naive and EM cells. However, both under normoxic and hypoxic conditions, glucose was critical for EM CD4+ T cell survival. Mechanistically, in the absence of glycolysis, mitochondrial membrane potential (ΔΨm) of EM cells declined and intrinsic apoptosis was triggered. Restoring pyruvate levels, the end product of glycolysis, preserved ΔΨm and prevented apoptosis. Furthermore, reconstitution of reactive oxygen species (ROS), whose production depends on ΔΨm, also rescued viability, whereas scavenging mitochondrial ROS exacerbated apoptosis. Rapid access of SRC in hypoxia, linked with built-in, oxygen-resistant glycolytic reserve that functionally insulates ΔΨm and mitochondrial ROS production from oxygen tension changes, provides an immune-metabolic basis supporting survival, migration, and function of EM CD4+ T cells in normoxic and hypoxic conditions.

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Section: Discussionmentioning

confidence: 99%

The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions

Dimeloe

Mehling

Frick

et al. 2016

The Journal of Immunology

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“…Recently, mitochondrial activation has been reported to be critical for generation of T-cell proliferation and memory formation by studies in vitro (17) as well as in vivo (18). T-cell receptor signaling induces Ca 2+ release, which in turn promotes mitochondrial activities including the tricarboxylic acid (TCA) cycle and reactive oxygen species (ROS) generation (19).…”

Section: Significancementioning

confidence: 99%

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

Chamoto

Chowdhury

Kumar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

326

287

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Although immunotherapy by PD-1 blockade has dramatically improved the survival rate of cancer patients, further improvement in efficacy is required to reduce the fraction of less sensitive patients. In mouse models of PD-1 blockade therapy, we found that tumor-reactive cytotoxic T lymphocytes (CTLs) in draining lymph nodes (DLNs) carry increased mitochondrial mass and more reactive oxygen species (ROS). We show that ROS generation by ROS precursors or indirectly by mitochondrial uncouplers synergized the tumoricidal activity of PD-1 blockade by expansion of effector/ memory CTLs in DLNs and within the tumor. These CTLs carry not only the activation of mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) but also an increment of their downstream transcription factors such as PPAR-gamma coactivator 1α (PGC-1α) and T-bet. Furthermore, direct activators of mTOR, AMPK, or PGC-1α also synergized the PD-1 blockade therapy whereas none of above-mentioned chemicals alone had any effects on tumor growth. These findings will pave a way to developing novel combinatorial therapies with PD-1 blockade.PD-1 | cancer immunotherapy | mitochondria | immune metabolism | PGC-1α

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“…ROS generated from Nox2, Duox1 and mitochondria in T cells were reported to be relevant to these functions [9,10,40]. ROS from macrophages and other immune cells are also involved [41].…”

Section: ) Signaling Role In T Cell Tolerancementioning

confidence: 99%

Roles of Reactive Oxygen Species in Rheumatoid Arthritis Pathogenesis

Yoo

Kim

et al. 2016

J Rheum Dis

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Rheumatoid arthritis (RA) is an autoimmune disease that starts with decreased tolerance to modified self-antigens and eventually leads to synovitis and destruction of bone and cartilage. Age is a risk factor for developing RA. Major changes in the immune system come with age due to chronic oxidative stress on the deoxyribonucleic acid (DNA) damage pathway, somatic mutation, modifications of auto-antigens, T cell tolerance and activation of fibroblast-like synoviocytes (FLS). Reactive oxygen species (ROS) generated by nicotinamide adenine dinucleotide phosphate oxidase 2 (NADPH oxidase 2) suppress T cell receptor signaling. Sirtuin 1 (SIRT1) is a critical immune suppressor of T cell activation and a key regulator of oxidative stress. When oxidative stress reduces activity of SIRT1, the breakdown of tolerance to modified self-antigens is expected. Generation of ROS can be perpetuated by enhanced DNA damage and dysfunctional mitochondria in a feedback loop during the development of RA. Through major T cell loss and selective proliferation of peripheral T cells, pro-inflammatory T cell pools with abnormal features are established in the T cell compartment. Hypoxic and inflammatory condition in synovium perpetuates ROS generation, which leads to the activation of FLS. In both T cell and synovium compartment, oxidative stress reshapes the immune system into the development of pre-clinical RA. (J Rheum Dis 2016;23:340-347)

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

Cited by 1,042 publications

References 48 publications

The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions

The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

Roles of Reactive Oxygen Species in Rheumatoid Arthritis Pathogenesis

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