L Redox Mediated Amplification of Immune Responses

Immune responses against environmental pathogens typically involve the lymphocyte receptors for antigen, receptors for costimulatory signals, and various cytokine receptors [149,150]. In addition, the immune response is subject to regulation by redox processes due to the various redox-sensitive signaling pathways discussed in the previous section. The activation of T-cell functions is strongly enhanced by ROS and/or by an oxidative shift in the intracellular glutathione REDST [62,106]. Superoxide and/or physiologically relevant concentrations of hydrogen peroxide were shown to augment the production of IL-2 by antigenically or mitogenically stimulated T lymphocytes in various experimental systems [105,136]. In addition, low micromolar concentrations of hydrogen peroxide were found to induce the expression of the IL-2 receptor in mouse T-lineage cells [105].

The amplifying effect of ROS has long been ignored by immunologists because T-cell functions, such as IL-2 production, can be readily induced by sufficiently high concentrations of antigen or antibodies that bind to the T-cell receptors and the co-stimulatory receptor CD28 in the absence of additional ROS [100]. In T cells, strong activation of the co-stimulatory receptor CD28 causes a significant decrease in intracellular glutathione levels and the endogenous production of hydrogen peroxide [37,105]. In B lymphocytes, ROS production was shown to be induced by ligation of the CD40 receptor [96]. In a typical immune response against environmental pathogens in vivo, however, high ligand concentrations for the various lymphocyte receptors may be the exception rather than the rule, because the antigen concentrations are relatively small in the initial phase of the infection. ROS production by activated macrophages or neutrophils in the inflammatory environment may therefore be decisive for the survival of the infected host, because it amplifies the signaling cascades and decreases thereby the antigen thresholds required for lymphocyte activation. Importantly, physiologically relevant concentrations of ROS or other inducers of moderate oxidative stress were found to amplify the signaling cascades after relatively weak stimulation of the antigen receptor but did not replace the signal from the CD28 costimulatory receptor.

To reconcile the seemingly conflicting redox requirements for the induction and execution of signaling processes (see previous section), the immune system requires, on the average, a delicately balanced intermediate redox state [40]. A study on healthy human subjects showed that persons with intermediate intracellular glutathione levels (20-30 nM/mg protein) had higher CD4+ and higher CD8+ T-cell numbers than persons with either lower or higher glutathione levels [85]. However, lymphocytes are extremely mobile and may migrate from an oxidative inflammatory environment into a more reducing environment in the course of an immune response. Experiments with cultured T cells have shown that activation of AP-1 and NF-kB transcription factors is strongly enhanced when cells are stimulated under relatively oxidative conditions and shifted after 1 hour to more reducing conditions [46]. This effect of the shift in redox condition may be viewed as an additional fail-safe mechanism against the undesirable activation of immune reactions, for example, against autoantigens. In line with the differential redox requirement in the induction and execution phase of the signaling cascade, it was found that simultaneous injection of glutathione suppressed the in vivo immunization by small numbers of stimulator cells (i.e., small amounts of antigen) but enhanced the in vivo immunization with relatively large numbers of stimulator cells [137].

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