Serial Review: Reactive Oxygen Species in Immune ResponsesT Cell Receptor Stimulation, Reactive Oxygen Species, and Cell Signaling☆
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.
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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.
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Present address: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.