Yang Di, Wang Huiming, Ni Bing, He Yani, Li Jingyi, Tang Yuyu, Fu Xiaolan, Wang Qinghong, Xu Guilian, Li Kailong, Yang Zhao, Wu Yuzhang
The Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, PR China.
Mol Immunol. 2009 Apr;46(7):1432-42. doi: 10.1016/j.molimm.2008.12.010. Epub 2009 Feb 5.
The activating receptor NKG2D is mainly expressed by human CD8(+) T cells and NK cells but normally absent on CD4(+) T cells. However, a subset of autoreactive NKG2D(+)CD4(+) T cells has been found to exist in some autoimmune disease such as rheumatoid arthritis (RA) and to participate in the imbalance of immune response and inflammation. Up to date this observation has been extended to some autoimmune diseases such as RA and Crohn's disease and the mechanism underlying the presence of this type of NKG2D(+)CD4(+) T cells has not been delineated yet. In this study, we found that a substantial proportion of CD4(+) T cells expressed NKG2D in the PBMC of SLE patients. We also found that monocytes in SLE aberrantly expressed the NKG2D ligand of MHC class I chain-related (MIC) molecules and membrane-bound IL-15 (mIL-15) at the cell surface. When cultured with the sera from SLE patients, the monocytes from healthy volunteers could be induced to express MIC and mIL-15. However, this induced expression of MIC and mIL-15 could be blocked with anti-IFN-gamma receptor (anti-IFN-gammaR) antibody. We further demonstrated that NKG2D could be induced on normal CD4(+) T cells either cocultured with monocytes from patients with SLE, or monocytes from healthy volunteers but pretreated with IFN-gamma. Moreover, Th1 cytokines were found to be produced by NKG2D(+)CD4(+) T cells in the coculture system. By transwell assay, we found that both NKG2D expression and Th1 cytokines production depended on the cell-cell contact. These results indicate that the elevated sera IFN-gamma may be responsible for MIC and mIL-15 induction on monocytes in SLE; mIL-15 on monocytes contribute to NKG2D receptor induction on a subset of CD4(+) T cells. Moreover, CD14(+) monocytes promote NKG2D(+)CD4(+) T cells activation through the NKG2D-MIC engagement in the pathogenesis of SLE.
激活受体NKG2D主要由人CD8(+) T细胞和NK细胞表达，但在CD4(+) T细胞上通常不存在。然而，已发现一部分自身反应性NKG2D(+)CD4(+) T细胞存在于某些自身免疫性疾病中，如类风湿性关节炎（RA），并参与免疫反应和炎症的失衡。迄今为止，这一观察结果已扩展到一些自身免疫性疾病，如RA和克罗恩病，而这类NKG2D(+)CD4(+) T细胞存在的潜在机制尚未阐明。在本研究中，我们发现SLE患者外周血单个核细胞（PBMC）中相当一部分CD4(+) T细胞表达NKG2D。我们还发现SLE患者的单核细胞在细胞表面异常表达MHC I类链相关（MIC）分子的NKG2D配体和膜结合IL-15（mIL-15）。当与SLE患者的血清一起培养时，健康志愿者的单核细胞可被诱导表达MIC和mIL-15。然而，这种诱导的MIC和mIL-15表达可被抗干扰素-γ受体（抗IFN-γR）抗体阻断。我们进一步证明，正常CD4(+) T细胞与SLE患者的单核细胞或经IFN-γ预处理的健康志愿者的单核细胞共培养时，可诱导NKG2D表达。此外，在共培养系统中发现NKG2D(+)CD4(+) T细胞可产生Th1细胞因子。通过Transwell实验，我们发现NKG2D表达和Th1细胞因子产生均依赖于细胞间接触。这些结果表明，SLE患者血清中升高的IFN-γ可能是导致单核细胞诱导表达MIC和mIL-15的原因；单核细胞上的mIL-15有助于诱导一部分CD4(+) T细胞上的NKG2D受体。此外，在SLE发病机制中，CD14(+)单核细胞通过NKG2D-MIC相互作用促进NKG2D(+)CD4(+) T细胞活化。
