Oxidative Stress Mediates a Reduced Expression of the Activating Receptor NKG2D in NK Cells from End-Stage Renal Disease Patients

Abstract

To characterize the immune defect of patients with end-stage renal disease (ESRD), we performed NK cell subset analysis in 66 patients with ESRD treated by hemodialysis (n = 59) or peritoneal dialysis (n = 7). Compared with healthy blood donors, patients undergoing chronic dialysis showed a profound decrease in NKG2D+ cells within both the CD8+ T cell (58% vs 67%, p = 0.03) and NK cell (39% vs 56%, p = 0.002) populations. CD56dim cells, which comprise the majority of NK cells in the periphery, were more affected in this regard than were CD56bright cells. Uremic serum could decrease NKG2D expression on NK cells from healthy donors. Among factors that could contribute to the decrease in NKG2D expression in ESRD patients, reactive oxygen species (ROS) play a major role. We found that catalase could reverse the effects of uremic serum on NKG2D expression (p < 0.001) and that ROS down-regulated NKG2D at the mRNA level and at the NK cell surface. Additionally, ESRD patients had both increased membrane-bound MHC class I-related chain A (MICA) on monocytes (p = 0.04) and increased soluble MICA (203 pg/ml vs 110 pg/ml; p < 0.001). Both ROS and uremic serum could significantly increase in vitro the expression of the NKG2D ligand MICA on the renal epithelial cell line HK-2. Taken together, these studies suggest for the first time that both low NKG2D expression and up-regulation of its ligand MICA are related to ROS production and may be involved in the immune deficiency of ESRD patients.

DNAM-1 ligand expression on Ag-stimulated T lymphocytes is mediated by ROS-dependent activation of DNA-damage response: relevance for NK–T cell interaction

“…Conversely, oxidative stress has been previously found to induce NKG2DL expression in other cell systems. 27,28,41 These findings highlight the complexity of the molecular mechanisms leading to the induction of different ligands for distinct NK-activating receptors, and further support the notion that they may involve common or distinct pathways depending on the form of stress, the type of ligand, and the cellular context.Our study also shows that monocytes are the main cellular source of ROS that regulate PVR expression during Ag-induced T-cell proliferation. Indeed, we observed reduced levels of PVR on proliferating T cells cultured in the context of CD14 ϩ cell-depleted PBMCs, which were almost completely restored upon addition of H 2 O 2 .…”

Reactive Oxygen Species– and DNA Damage Response–Dependent NK Cell Activating Ligand Upregulation Occurs at Transcriptional Levels and Requires the Transcriptional Factor E2F1

“…Given the importance of changes in the endogenous cellular redox for DDR activation in response to several DNA damaging agents including DOX and MEL (27,28,40), and because most studies addressing the role of oxidative stress in the regulation of NKG2D and DNAM-1 ligands rely on the exposure to exogenous sources of ROS (i.e., H 2 O 2 ) or to exogenous exposure of endogenously produced ROS (25,41,42), we tested whether the druginduced activation of DDR cascade underlying the enhancement of MICA, MICB, and PVR expression was dependent on ROS signaling. We demonstrated that DOX-and MEL-dependent change in the redox state is the major event triggering the activation of the DDR pathway and leads to activating NK receptor ligand upregulation on MM cells.…”

MICA/B expression in macrophage foam cells infiltrating atherosclerotic plaques

“…Recent work has shown that various cellular stresses such as reactive oxygen species and DNA damage up-regulate MICA/B expression (Peraldi et al, 2009) and that dysregulated 5 expression of NKG2D ligands is involved in the development of inflammatory and autoimmune diseases such as rheumatoid arthritis, celiac disease and type 1 diabetes (Groh et al, 2003;Meresse et al, 2004;Ogasawara et al, 2004).…”