Institute of Immunology, PLA, Third Military Medical University, Chongqing, 400038, P.R. China.
Department of Pathophysiology and High Altitude Pathology/Key Laboratory of High Altitude Environment Medicine (Third Military Medical University), Ministry of Education/Key Laboratory of High Altitude Medicine, College of High Altitude Military Medicine, Third Military Medical University, Chongqing, 400038, P.R. China.
Sci Rep. 2017 Apr 28;7(1):1288. doi: 10.1038/s41598-017-01379-y.
Systemic lupus erythematosus (SLE) features a decreased pool of CD4CD25Foxp3 T regulatory (Treg) cells. We had previously observed NKG2DCD4 T cell expansion in contrast to a decreased pool of Treg cells in SLE patients, but whether NKG2DCD4 T cells contribute to the decreased Treg cells remains unclear. In the present study, we found that the NKG2DCD4 T cells efficiently killed NKG2D ligand (NKG2DL) Treg cells in vitro, whereby the surviving Treg cells in SLE patients showed no detectable expression of NKG2DLs. It was further found that MRL/lpr lupus mice have significantly increased percentage of NKG2DCD4 T cells and obvious decreased percentage of Treg cells, as compared with wild-type mice. Adoptively transferred NKG2DL Treg cells were found to be efficiently killed in MRL/lpr lupus mice, with NKG2D neutralization remarkably attenuating this killing. Anti-NKG2D or anti-interferon-alpha receptor (IFNAR) antibodies treatment in MRL/lpr mice restored Treg cells numbers and markedly ameliorated the lupus disease. These results suggest that NKG2DCD4 T cells are involved in the pathogenesis of SLE by killing Treg cells in a NKG2D-NKG2DL-dependent manner. Targeting the NKG2D-NKG2DL interaction might be a potential therapeutic strategy by which Treg cells can be protected from cytolysis in SLE patients.
系统性红斑狼疮（SLE）的特征是 CD4CD25Foxp3 T 调节（Treg）细胞池减少。我们之前观察到，SLE 患者中 NKG2DCD4 T 细胞扩增，而 Treg 细胞池减少，但 NKG2DCD4 T 细胞是否有助于 Treg 细胞减少尚不清楚。在本研究中，我们发现 NKG2DCD4 T 细胞在体外能有效杀伤 NKG2D 配体（NKG2DL）Treg 细胞，而 SLE 患者中存活的 Treg 细胞则没有检测到 NKG2DL 的表达。进一步发现，与野生型小鼠相比，MRL/lpr 狼疮小鼠的 NKG2DCD4 T 细胞比例显著增加，Treg 细胞比例明显降低。实验发现，NKG2DL Treg 细胞在 MRL/lpr 狼疮小鼠中被有效杀伤，而 NKG2D 中和抗体可显著减弱这种杀伤作用。在 MRL/lpr 小鼠中使用抗 NKG2D 或抗干扰素-α受体（IFNAR）抗体治疗可恢复 Treg 细胞数量，并显著改善狼疮疾病。这些结果表明，NKG2DCD4 T 细胞通过 NKG2D-NKG2DL 依赖性方式杀伤 Treg 细胞，从而参与 SLE 的发病机制。靶向 NKG2D-NKG2DL 相互作用可能是一种潜在的治疗策略，可以保护 SLE 患者的 Treg 细胞免受细胞溶解。
