Dataset Information

NKG2D⁺CD4⁺ T Cells Kill Regulatory T Cells in a NKG2D-NKG2D Ligand- Dependent Manner in Systemic Lupus Erythematosus.

ABSTRACT: Systemic lupus erythematosus (SLE) features a decreased pool of CD4⁺CD25⁺Foxp3⁺ T regulatory (Treg) cells. We had previously observed NKG2D⁺CD4⁺ T cell expansion in contrast to a decreased pool of Treg cells in SLE patients, but whether NKG2D⁺CD4⁺ T cells contribute to the decreased Treg cells remains unclear. In the present study, we found that the NKG2D⁺CD4⁺ 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 NKG2D⁺CD4⁺ 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 NKG2D⁺CD4⁺ 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.

SUBMITTER: Yang D

PROVIDER: S-EPMC5430709 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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NKG2D+CD4+ T Cells Kill Regulatory T Cells in a NKG2D-NKG2D Ligand- Dependent Manner in Systemic Lupus Erythematosus.

Yang Di D Tian Zhiqiang Z Zhang Mengjie M Yang Weibing W Tang Jun J Wu Yuzhang Y Ni Bing B

Scientific reports 20170428 1

Systemic lupus erythematosus (SLE) features a decreased pool of CD4+CD25+Foxp3+ T regulatory (Treg) cells. We had previously observed NKG2D+CD4+ T cell expansion in contrast to a decreased pool of Treg cells in SLE patients, but whether NKG2D+CD4+ T cells contribute to the decreased Treg cells remains unclear. In the present study, we found that the NKG2D+CD4+ T cells efficiently killed NKG2D ligan ...[more]

PMID: 28455530

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Project description:Objective: The mechanism of CD4+ T-cell dysfunction in systemic lupus erythematosus (SLE) has not been fully understood. Increasing evidence show that long noncoding RNAs (lncRNAs) can regulate immune responses and take part in some autoimmune diseases, while little is known about the lncRNA expression and function in CD4+ T of SLE. Here, we aimed to detect the expression profile of lncRNAs in lupus CD4+ T cells and explore the mechanism that how lincRNA00892 in CD4+ T cells is involved in the pathogenesis of SLE. Methods: The expression profiles of lncRNAs and mRNAs in CD4+ T cells from SLE patients and healthy controls were detected by microarray. LincRNA00892 and CD40L were chosen for validation by quantitative real-time PCR (qRT-PCR). Coexpression network was conducted to predict the potential target genes of lincRNA00892. Then lincRNA00892 was overexpressed in normal CD4+ T cells via lentivirus transfection. The expression of lincRNA00892 was detected by qRT-PCR. The expression of CD40L was detected by qRT-PCR, western blotting, and flow cytometry, respectively. The expression of CD69 and CD23 was measured by flow cytometry. The secretion of IgG was determined by enzyme-linked immunosorbent assay (ELISA). The proteins targeted by lincRNA00892 were measured by RNA pulldown and subsequent mass spectrometry (MS). The interaction between heterogeneous nuclear ribonucleoprotein K (hnRNP K) and lincRNA00892 or CD40L was detected by RNA immunoprecipitation (RIP) assay. Results: A total of 1887 lncRNAs and 3375 mRNAs were found to be aberrantly expressed in CD4+ T cells of SLE patients compared to healthy controls. LincRNA00892 and CD40L were confirmed to be upregulated in CD4+ T cells of SLE patients by qRT-PCR. The lncRNA-mRNA coexpression network analysis indicated that CD40L was a potential target of lincRNA00892. Overexpression of lincRNA00892 enhanced CD40L protein levels while exerting little influence on CD40L mRNA levels in CD4+ T cells. In addition, lincRNA00892 could induce the activation of CD4+ T cells. Furthermore, lincRNA00892 led to the activation of B cells and subsequent secretion of IgG in a CD4+ T-cell-dependent manner. Finally, hnRNP K was found to be among the proteins pulled down by lincRNA00892, and hnRNP K could bind to lincRNA00892 or CD40L directly. Conclusion: Our results showed that the lncRNA expression profile was altered in CD4+ T cells of SLE. LincRNA00892 possibly contributed to the pathogenesis of SLE by targeting hnRNP K and subsequently upregulating CD40L expression to activate CD4+ T and B cells. These provided us a potential target for further mechanistic studies of SLE pathogenesis.

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Dataset Information

NKG2D⁺CD4⁺ T Cells Kill Regulatory T Cells in a NKG2D-NKG2D Ligand- Dependent Manner in Systemic Lupus Erythematosus.

Publications

NKG2D<sup>+</sup>CD4<sup>+</sup> T Cells Kill Regulatory T Cells in a NKG2D-NKG2D Ligand- Dependent Manner in Systemic Lupus Erythematosus.

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