Elsevier

Free Radical Biology and Medicine

Volume 37, Issue 8, 15 October 2004, Pages 1144-1151
Free Radical Biology and Medicine

Serial Review: Reactive Oxygen Species in Immune Responses
T Cell Receptor Stimulation, Reactive Oxygen Species, and Cell Signaling

https://doi.org/10.1016/j.freeradbiomed.2004.05.029Get rights and content

Abstract

In the immune system, much of the focus on reactive oxygen species (ROS) has been regarding their role in antimicrobial defense as part of the innate immune system. In addition to this role, it is now becoming clear that ROS are used by cells of the adaptive immune system as regulators of signal transduction by cell surface receptors. The activation of T lymphocytes through their specific antigen receptor [T cell receptor (TCR)] is vital in regulating the immune response. Much experimental evidence has suggested that activation of T cells is redox dependent and recent studies have shown that engagement of the TCR induces rapid production of ROS. This review examines the evidence for TCR-stimulated generation of ROS and discusses the role(s) of receptor-stimulated ROS production in T cell signal transduction and gene expression.

Introduction

T cells play critical roles in the immune response against infectious agents and tumor development. For an optimal and appropriate immune response, T cells require activation through the T cell receptor (TCR), which recognizes specific antigen presented in the context of major histocompatibility complex (MHC). This recognition also confers the ability of T cell responses to distinguish between “self” and “nonself.” Engagement of the TCR, throughout the lifetime of the T cell, controls the survival, proliferation, and/or differentiation of T cells. Thus, signaling through the TCR has important consequences for proper channeling of the immune response and the effectiveness of that response. The focus of this review will be on reactive oxygen species (ROS) generation in T cells, in particular the observation that signals through the TCR or those that lead to T cell activation induce ROS production.

Stimulation of cognate receptors, with ligands as diverse as TGF-β [1], insulin [2], angiotensin II [3], and EGF [4], induces the intracellular production of ROS. In these studies, ROS function as requisite second messengers that are necessary for ligand-mediated regulation of protein kinase activation, gene expression, and/or proliferative responses. Accumulating evidence has also indicated that ROS production induces cell proliferation and transformation [5], [6], [7], [8], [9]. Studies over the past few years on the redox regulation of T cell signaling and T cell responses have expanded the understanding that T cells also produce ROS upon TCR stimulation. Furthermore, the data indicate that these reactive species are then important in the regulation of T cell signal transduction, gene expression, and function.

Section snippets

Oxidant dependence of T cell activation

The earliest suggestion for a role of ROS production in T cell activation was from experiments testing the effects of pharmacologic antioxidants on primary T cell activation induced by mitogens, antibodies to the TCR or antigens. T cell activation and proliferation require coordinated activation of protein kinases, transcription factors, and the production of cytokines. Mitogens induce strong T cell proliferation, and the addition of antioxidants to the cultures inhibited proliferation and

ROS production in activated T cells

The effects of treatment with antioxidants, however, are insufficient as a sole indicator of ROS production. It is necessary to demonstrate that T cells do indeed produce ROS upon TCR signaling using other methods.

In the immune system, ROS production has been studied extensively in phagocytic cells including macrophages and neutrophils. However, by using mitogenic stimulation (such as PMA and ConA), increased chemiluminescence was observed in cells derived from the thymus [19] or canine spleen

Species of oxidant(s) produced by TCR stimulation

Oxidation-sensitive dyes exhibit some selectivity in their oxidation by discrete reactive species in an isolated system. Nevertheless, they are oxidized by multiple species of oxidants [22], [38], and their oxidation/fluorescence can be modulated by intracellular changes in pH or calcium [39]. Thus, identification of the actual species of oxidant(s) produced in T cells has yet to be described. Pharmacologic antioxidants, while often used to assess the role(s) of ROS, have also been used to

Source(s) of ROS in T cells

As molecular characterization of the species of oxidants generated upon TCR signaling is relatively unclear, the sources of ROS or signals that control TCR-stimulated ROS production are also unexplored. TCR signaling involves a complex web of protein kinases, phospholipases, GTP-binding proteins, and adapter proteins (reviewed in [44]).

In non–T cells, lipid metabolism, mitochondria, and/or NAD(P)H oxidases have been shown to be common sources of ROS. The limited existing data suggest that T

Is ROS production from T cells derived from contaminating cells?

The evaluation of ROS function and/or production in T cells has, depending on the study, used “purified” T cells (>90% T cells), partially purified cells, or mixed cell preparations from lymphoid organs. In other situations, cells have been stimulated with antigen (peptide or superantigen) presented by APCs [30]. In each of these settings, the possibility exists for ROS production by non–T cells present in the assays, and some studies have actually proposed that ROS are not generated by T cells

Biological/biochemical role(s) of TCR-stimulated ROS production

As noted above, there is still conflicting evidence about the effects and/or roles of ROS in T cell function. Numerous studies have exposed T cells to exogenous oxidative stress to study how redox-sensitive targets in T cells may be affected in zones of inflammation or oxidative stress [53], [54]. The biological effects and targets identified in these studies often have differed from those effects observed in cells stimulated only in the presence of antioxidants. Both types of approaches are

Acknowledgements

We thank the American Heart Association for its support. We also apologize to any authors whose works were omitted from this review due to space limitations.

References (81)

  • J. Kwon et al.

    T cell receptor–stimulated generation of hydrogen peroxide inhibits MEK-ERK activation and lck serine phosphorylation

    Free Radic. Biol. Med

    (2003)
  • H. Rabesandratana et al.

    Increased oxidative metabolism in PMA-activated lymphocytes: a flow cytometric study

    Int. J. Immunopharmacol

    (1992)
  • S. Walrand et al.

    Flow cytometry study of polymorphonuclear neutrophil oxidative burst: a comparison of three fluorescent probes

    Clin. Chim. Acta

    (2003)
  • M. Broillet et al.

    Photoactivation and calcium sensitivity of the fluorescent NO indicator 4,5-diaminofluorescein (DAF-2): implications for cellular NO imaging

    FEBS Lett

    (2001)
  • B.J. Day et al.

    Manganic porphyrins possess catalase activity and protect endothelial cells against hydrogen peroxide–mediated injury

    Arch. Biochem. Biophys

    (1997)
  • B. Banfi et al.

    A Ca(2+)-activated NADPH oxidase in testis, spleen, and lymph nodes

    J. Biol. Chem

    (2001)
  • D.M. van Reyk et al.

    The intracellular oxidation of 2′,7′-dichlorofluorescin in murine T lymphocytes

    Free Radic. Biol. Med

    (2001)
  • S. Cemerski et al.

    Reactive oxygen species differentially affect T cell receptor–signaling pathways

    J. Biol. Chem

    (2002)
  • T. Finkel

    Oxidant signals and oxidative stress

    Curr. Opin. Cell Biol

    (2003)
  • G.F. Weber et al.

    A signaling pathway coupled to T cell receptor ligation by MMTV superantigen leading to transient activation and programmed cell death

    Immunity

    (1995)
  • S.D. Goldstone et al.

    Redox regulation of the mitogen-activated protein kinase pathway during lymphocyte activation

    Biochim. Biophys. Acta

    (1997)
  • S.D. Goldstone et al.

    Transcription factors as targets for oxidative signalling during lymphocyte activation

    Biochim. Biophys. Acta

    (1995)
  • T.C. Meng et al.

    Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo

    Mol. Cell

    (2002)
  • S.R. Lee et al.

    Reversible inactivation of protein-tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor

    J. Biol. Chem

    (1998)
  • G.L. Schieven et al.

    Reactive oxygen intermediates activate NF-κB in a tyrosine kinase–dependent mechanism and in combination with vanadate activate the p56lck and p59fyn tyrosine kinases in human lymphocytes

    Blood

    (1993)
  • M.A. Kang et al.

    Rosmarinic acid inhibits Ca2+-dependent pathways of T-cell antigen receptor–mediated signaling by inhibiting the PLC-γ1 and I tk activity

    Blood

    (2003)
  • V.J. Thannickal et al.

    Ras-dependent and -independent regulation of reactive oxygen species by mitogenic growth factors and TGF-β1

    FASEB J

    (2000)
  • M. Sundaresan et al.

    Requirement for generation of H2O2 for platelet-derived growth factor signal transduction

    Science

    (1995)
  • K. Irani et al.

    Mitogenic signaling mediated by oxidants in ras-transformed fibroblasts

    Science

    (1997)
  • Y.A. Suh et al.

    Cell transformation by the superoxide-generating oxidase Mox1

    Nature

    (1999)
  • R.H. Burdon

    Control of cell proliferation by reactive oxygen species

    Biochem. Soc. Trans

    (1996)
  • R.S. Arnold et al.

    Hydrogen peroxide mediates the cell growth and transformation caused by the mitogenic oxidase Nox1

    Proc. Natl. Acad. Sci. USA

    (2001)
  • A. Novogrodsky et al.

    Hydroxyl radical scavengers inhibit lymphocyte mitogenesis

    Proc. Natl. Acad. Sci. USA

    (1982)
  • J. Dornand et al.

    Inhibition of murine T-cell responses by antioxidants: the targets of lipo-oxygenase pathway inhibitors

    Immunology

    (1989)
  • G. Chaudhri et al.

    Effect of antioxidants on primary alloantigen-induced T cell activation and proliferation

    J. Immunol

    (1986)
  • J. Schmielau et al.

    Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of t-cell function in advanced cancer patients

    Cancer Res

    (2001)
  • D.A. Patterson et al.

    Hydrogen peroxide–mediated inhibition of T-cell response to mitogens is a result of direct action on T cells

    Arch. Surg

    (1988)
  • D.D. Duncan et al.

    Oxidatively stressed lymphocytes remain in G0/G1a on mitogenic stimulation

    J. Biochem. Toxicol

    (1990)
  • K. Wrogemann et al.

    Chemiluminescence and immune cell activation: I. Early activation of rat thymocytes can be monitored by chemiluminescence measurements

    Eur. J. Immunol

    (1978)
  • D.A. Hume et al.

    Concanavalin A–induced chemiluminescence in rat thymus lymphocytes. Its origin and role in mitogenesis

    Biochem. J

    (1981)
  • Cited by (139)

    • Harnessing immune response using reactive oxygen Species-Generating/Eliminating inorganic biomaterials for disease treatment

      2022, Advanced Drug Delivery Reviews
      Citation Excerpt :

      A number of previous studies have proved that antioxidants could significantly inhibit the activation and proliferation of T cells that can be induced by T cell receptor (TCR) antibodies. TCR activation is often accompanied with the generation of ROS [55]. Upon TCR stimulation, the generation of ROS (including H2O2 and O2−) can start as early as 2–4 min, thereby indicating the potential impact of ROS in TCR signaling [56].

    • Myeloid related proteins are up-regulated in autoimmune thyroid diseases and activate toll-like receptor 4 and pro-inflammatory cytokines in vitro

      2018, International Immunopharmacology
      Citation Excerpt :

      Autoimmune-correlated inflammation may cause the excessive expression of ROS, thus enhancing oxidative stress in the thyroid via lymphocyte infiltration [25,26]. Activated lymphocytes also promote the accumulation of ROS which can cause oxidative damage to the thyroid gland [27]. In this way, antioxidants are present in human serum erythrocytes and in the tissues, act to prevent the damage caused by excessive levels of ROS [28,29].

    View all citing articles on Scopus

    This article is part of a series of reviews on “Reactive Oxygen Species in Immune Responses.” The full list of papers may be found on the home page of the journal.

    1

    Present address: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

    View full text