in Immune Network Immune Netw 1598-2629 2092-6685 Korean Association of Immunologists 10.4110/in.2018.18.e14 in-18-e14 Review Article The Role of Reactive Oxygen Species in Regulating T Cell-mediated Immunity and Disease YaroszEmily L. ChangCheong-Hee * Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA Correspondence to Cheong-Hee Chang Department of Microbiology and Immunology, University of Michigan Medical School, 5641 Medical Science Building II, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA. E-mail: heechang@umich.edu

Conflict of Interest The authors declare no potential conflicts of interest.

 02 2018 04 02 2018 18 1 e14 12112017 15022018 19022018 Copyright © 2018 The Korean Association of Immunologists 2018 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract

T lymphocytes rely on several metabolic processes to produce the high amounts of energy and metabolites needed to drive clonal expansion and the development of effector functions. However, many of these pathways result in the production of reactive oxygen species (ROS), which have canonically been thought of as cytotoxic agents due to their ability to damage DNA and other subcellular structures. Interestingly, ROS has recently emerged as a critical second messenger for T cell receptor signaling and T cell activation, but the sensitivity of different T cell subsets to ROS varies. Therefore, the tight regulation of ROS production by cellular antioxidant pathways is critical to maintaining proper signal transduction without compromising the integrity of the cell. This review intends to detail the common metabolic sources of intracellular ROS and the mechanisms by which ROS contributes to the development of T cell-mediated immunity. The regulation of ROS levels by the glutathione pathway and the Nrf2-Keap1-Cul3 trimeric complex will be discussed. Finally, T cell-mediated autoimmune diseases exacerbated by defects in ROS regulation will be further examined in order to identify potential therapeutic interventions for these disorders.

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ROS modulate several aspects of T cell-mediated immunity downstream of TCR stimulation. (A) Following activation, signaling through the TCR stimulates the mitochondria to produce ROS, which in turn promote continued TCR signaling. The level of activation-induced ROS within the cell also critically affects the downstream functions of T cell proliferation, differentiation, and survival. Therefore, the modulation of ROS levels by cellular antioxidant pathways (e.g., GSH; Nrf2-Keap1-Cul3 trimeric complex) is crucial in maintaining proper T cell-mediated immunity. GSH regulates ROS levels by directly reducing free radicals encountered in the cytoplasm. In contrast, the Nrf2-Keap1-Cul3 trimeric complex disassociates upon sensing high levels of cellular ROS, allowing Nrf2 to enter the nucleus and activate the ARE-containing genes. (B) If cellular antioxidant pathways are dysregulated or mutated, cellular ROS levels will not be properly controlled. Therefore, high levels of ROS after T cell activation can lead to the development of several T cell-mediated autoimmune diseases and cancer. APC, antigen presenting cell; MHC, major histocompatibility complex.