Redox regulation of T-cell receptor signaling

Abstract

T-cell receptor (TCR) triggering by antigens activates a sophisticated intracellular signaling network leading to transcriptional activation, proliferation and differentiation of T cells. These events ultimately culminate in adaptive immune responses. Over recent years it has become evident that reactive oxygen species (ROS) play an important role in T-cell activation. It is now clear that ROS are involved in the regulation of T-cell mediated physiological and pathological processes. Upon TCR triggering, T cells produce oxidants, which originate from different cellular sources. In addition, within inflamed tissues, T cells are exposed to exocrine ROS produced by activated phagocytes or other ROS-producing cells. Oxidative modifications can have different effects on T-cell function. Indeed, they can stimulate T-cell activation but they can be also detrimental. These opposite effects of oxidation likely depend on different factors such as ROS concentration and source and also on the differentiation status of the T cells. Despite the well-stablished fact that ROS represent important modulators of T-cell activation, the precise molecular mechanisms of their action are far from clear. Here, we summarize the present knowledge on redox regulation of T-cell function with a particular emphasis on the redox regulation of TCR signaling.

Dual targeting of the thioredoxin and glutathione systems in cancer and HIV

“…An oxidative burst occurs immediately upon the encounter with the antigen (recently reviewed in ref. 21). This early oxidant burst leads Notwithstanding the above observations, there is growing evidence that Trx and GSH target different cysteines in the proteome, supporting the existence of nonredundant functions (12,13), as exemplified by the distinct mechanisms and roles of Trx and GSH in protein denitrosylation (7).…”

THEMIS: Two Models, Different Thresholds

“…The oxidized sulfenated active site cysteine thiol can subsequently be reduced and reactivated by glutathione and cytosolic redox regulatory proteins such as glutaredoxin, thioredoxin and peroxiredoxin. An important cellular mechanism for regulating protein tyrosine phosphatases is through localized production of ROS by cell surface NADPH oxidases that are co-activated with antigen receptor stimulation [33, 62]. …”

“…On the other hand, ROS (or cellular redox status) was not evaluated or used as a variable in the assays that reported enhanced TCR signaling responses in THEMIS deficient thymocytes and Jurkat T cells [13, 15]. ROS, generated intrinsically or by myeloid cells at sites of T cell activation have been shown to regulate lymphocyte signaling responses, in part by inhibiting PTPs including SHP-1 [33]. The role of ROS in the thymus has not been extensively examined; however, two studies indicate that ROS have a positive effect on T cell maturation [34, 35].…”

Clinical Value of Antioxidant Enzymes and Oxidative Biomarkers in Psoriasis

“…Patogenezde sorumlu olduğu düşünülen iki önemli neden immün aracılı gelişen kompleks bir bozukluk ve oksidatif strese bağlı artmış serbest radikal oluşumu yanı sıra antioksidan sistem ile arasındaki dengenin bozulmasıdır (2)(3)(4)(5) .…”