Increased oxidative stress contributes to impaired peripheral CD56^dimCD57⁺ NK cells from patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is characterized by loss of immune tolerance and imbalance of immune cell subsets. Natural killer (NK) cells contribute to regulate both the innate and adaptive immune response. In this study, we aimed to detect alterations of peripheral NK cells and explore intrinsic mechanisms involving in NK cell abnormality in SLE.

Blood samples from healthy controls (HCs) and patients with SLE and rheumatoid arthritis (RA) were collected. The NK count, NK subsets (CD56^bright, CD56^dimCD57^-, and CD56^dimCD57⁺), phenotypes, and apoptosis were evaluated with flow cytometer. Mitochondrial reactive oxygen species (mtROS) and total ROS levels were detected with MitoSOX Red and DCFH-DA staining respectively. Published data (GSE63829 and GSE23695) from Gene Expression Omnibus (GEO) was analyzed by Gene Set Enrichment Analysis (GSEA).

Total peripheral NK count was down-regulated in untreated SLE patients in comparison to that in untreated RA patients and HCs. SLE patients exhibited a selective reduction in peripheral CD56^dimCD57⁺ NK cell proportion, which was negatively associated with disease activity and positively correlated with levels of complement(C)3 and C4. Compared with HCs, peripheral CD56^dimCD57⁺ NK cells from SLE patients exhibited altered phenotypes, increased endogenous apoptosis and higher levels of mtROS and ROS. In addition, when treated with hydrogen peroxide (H₂O₂), peripheral CD56^dimCD57⁺ NK cell subset was more prone to undergo apoptosis than CD56^dimCD57^- NK cells. Furthermore, this NK cell subset from SLE patients exhibited impaired cytotoxicity in response to activated CD4⁺ T cells in vitro.

Our study demonstrated a selective loss of mature CD56^dimCD57⁺ NK cell subset in SLE patients, which may caused by preferential apoptosis of this subset under increased oxidative stress in SLE. The attenuated in vitro cytotoxicity of CD56^dimCD57⁺ NK cells may contribute to the impaired ability of eliminating pathogenic CD4⁺ T cells in SLE.