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

Yang, Di; Tian, Zhiqiang; Zhang, Mengjie; Yang, Wei‐Bing; Tang, Jun; Wu, Yuzhang; Ni, Bing

doi:10.1038/s41598-017-01379-y

Cited by 34 publications

(36 citation statements)

References 56 publications

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“…Groh et al showed that those cells promoted the cytotoxic damage against synoviocytes with anomalous expression of NKG2DLs ( 14 ). Later on, NKG2D+ CD4+ T cells have been associated with several other autoimmune diseases, such as Crohn’s disease ( 108 , 113 , 114 ), Wegener granulomatosis ( 115 , 116 ), type 2 diabetes ( 117 ), multiple sclerosis ( 118 ), and systemic lupus erythematosus (SLE) ( 119 , 120 ). Moreover, NKG2D+ CD4+ T cells accumulated in patients with MIC+ tumors ( 121 ) and cervical carcinoma ( 122 – 124 ).…”

Section: Nkg2d Expression On T Cell Subsets: When and Where?mentioning

confidence: 99%

“…However, increased frequencies of NKG2D+ CD4+ T cells inversely correlated with disease activity in juvenile-onset SLE, suggesting that these T cells may also have regulatory effects ( 134 ). Moreover, a recent study showed that NKG2D+ CD4+ T cells were involved in Treg killing in an NKG2D–NKG2DL-dependent manner in SLE ( 120 ).…”

Section: Nkg2d Expression On T Cell Subsets: When and Where?mentioning

confidence: 99%

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The NKG2D/NKG2DL Axis in the Crosstalk Between Lymphoid and Myeloid Cells in Health and Disease

2018

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Natural killer group 2, member D (NKG2D) receptor is a type II transmembrane protein expressed by both innate and adaptive immune cells, including natural killer (NK) cells, CD8+ T cells, invariant NKT cells, γδ T cells, and some CD4+ T cells under certain pathological conditions. NKG2D is an activating NK receptor that induces cytotoxicity and production of cytokines by effector cells and supports their proliferation and survival upon engagement with its ligands. In both innate and T cell populations, NKG2D can costimulate responses induced by other receptors, such as TCR in T cells or NKp46 in NK cells. NKG2D ligands (NKG2DLs) are remarkably diverse. Initially, NKG2DL expression was typically attributed to stressed, infected, or transformed cells, thus signaling “dysregulated-self.” However, many reports indicated their expression under homeostatic conditions, usually in the context of cell activation and/or proliferation. Myeloid cells, including macrophages and dendritic cells (DCs), are among the first cells sensing and responding to pathogens and tissue damage. By secreting a plethora of soluble mediators, by presenting antigens to T cells and by expressing costimulatory molecules, myeloid cells play vital roles in inducing and supporting responses of other immune cells in lymphoid organs and tissues. When activated, both macrophages and DCs upregulate NKG2DLs, thereby enabling them with additional mechanisms for regulating lymphocyte responses. In this review, we will focus on the expression of NKG2D by innate and adaptive lymphocytes, the regulation of NKG2DL expression on myeloid cells, and the contribution of the NKG2D/NKG2DL axis to the crosstalk of myeloid cells with NKG2D-expressing lymphocytes. In addition, we will highlight pathophysiological conditions associated with NKG2D/NKG2DL dysregulation and discuss the putative involvement of the NKG2D/NKG2DL axis in the lymphocyte/myeloid cell crosstalk in these diseases.

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Section: Nkg2d Expression On T Cell Subsets: When and Where?mentioning

confidence: 99%

Section: Nkg2d Expression On T Cell Subsets: When and Where?mentioning

confidence: 99%

The NKG2D/NKG2DL Axis in the Crosstalk Between Lymphoid and Myeloid Cells in Health and Disease

2018

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“…In addition to communication with, and regulation of, NK cells, it appears that expression of NKG2D ligands also makes macrophages susceptible to regulation by direct NKG2D-mediated killing. Autologous killing of macrophages and monocytes by NK cells or NKG2D-expressing CD4 + T cells was shown after induction of NKG2D ligand expression on monocytes by lipopolysaccharide (LPS) stimulation, in vitro culture with IL-10, or on monocytes from patients with systemic lupus erythematosus ( 44 – 46 ). Other observations include upregulation of NKG2D ligands by human monocytes, as well as murine macrophages and microglial cells, in response to GM-CSF and other myeloid growth factors, including FLT-3 ligand and stem cell factor ( 32 , 47 ).…”

Section: Function Of Nkg2d Ligand Expression By Monocytes and Macrophmentioning

confidence: 99%

More than Decoration: Roles for Natural Killer Group 2 Member D Ligand Expression by Immune Cells

Trembath

Markiewicz

2018

Front. Immunol.

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The activating immune receptor natural killer group 2 member D (NKG2D), which is expressed by natural killer cells and T cell subsets, recognizes a number of ligands expressed by “stressed” or damaged cells. NKG2D has been extensively studied for its role in tumor immunosurveillance and antiviral immunity. To date, the majority of studies have focused on NKG2D-mediated killing of target cells expressing NKG2D ligands. However, with a number of reports describing expression of NKG2D ligands by cells that are not generally considered stressed, it is becoming clear that some healthy cells also express NKG2D ligands. Expression of these ligands by cells within the skin, intestinal epithelium, and the immune system suggests other immune functions for NKG2D ligand expression in addition to its canonical role as a “kill me” signal. How NKG2D ligands function in this capacity is just now starting to be unraveled. In this review, we examine the expression of NKG2D ligands by immune cells and discuss current literature describing the effects of this expression on immunity and immune regulation.

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“…Moreover, these cells are thought to exert regulatory functions which may help to preserve self-tolerance, given that failure in the recognition and clearance of damaged cells can prolong the exposure of autoantigens and also the abnormal survival of activated immune cells [13][14][15]. Some studies have suggested that this constitutive expression might be reduced in lupus patients [12,18], while an enhancement in soluble MICA (sMICA) and other NKG2D ligands has been found in patients' sera [12,13]. Some studies have suggested that this constitutive expression might be reduced in lupus patients [12,18], while an enhancement in soluble MICA (sMICA) and other NKG2D ligands has been found in patients' sera [12,13].…”

Section: Introductionmentioning

confidence: 99%

“…Between NK-dependent homeostatic functions, a low expression of MICA in PBMC allows cross-talk with T helper cells and is probably involved in peripheral tolerance [13,16,17]. Some studies have suggested that this constitutive expression might be reduced in lupus patients [12,18], while an enhancement in soluble MICA (sMICA) and other NKG2D ligands has been found in patients' sera [12,13]. Interestingly, disruption of the MICA expression pathway is an immune evasion strategy evoked by intracellular pathogens and also by cancer cells, allowing their escape from cytotoxicity [10].…”

Section: Introductionmentioning

confidence: 99%

A subgroup of lupus patients with nephritis, innate T cell activation and low vitamin D is identified by the enhancement of circulating MHC class I-related chain A

Pérez-Ferro

Romero-Bueno

Castillo

et al. 2019

Clinical and Experimental Immunology

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The major histocompatibility complex (MHC) class I-related chain A (MICA) is induced upon stress, and labels malfunctioning cells for their recognition by cytotoxic lymphocytes. Alterations in this recognition and also abnormal natural killer (NK) functions have been found in systemic lupus erythematosus (SLE). MICA can be shed from cells, subsequently acting as a soluble decoy receptor (sMICA). Our purpose was to study circulating sMICA levels in relationship with the activation of innate pathways in PBMC in a cohort of lupus patients. NK cells were characterized by flow cytometry. Gene expression of Toll-like receptors (TLR), interferon (IFN)-I sensitive genes and MICA were separately analyzed in monocytes, T cells and B cells. Serum sMICA was measured with enzyme-linked immunosorbent assay (ELISA). In our cohort, NK cell counts dropped in relationship with disease activity. sMICA showed an inverse trend with NK cell counts, as well as a significant association with activity indices, but not with complement decrease. Levels of sMICA associated to proteinuria and active nephritis. A multivariate regression model revealed anti-nuclear antibody (ANA) titres, the up-regulation of TLR-4 in T cellsand lower vitamin D as predictors of sMICA enhancement. Interestingly, vitamin D showed an inverse association with proteinuria and a strong correlation with T cell MICA mRNA levels. According to our data, circulating sMICA identifies a subgroup of lupus patients with low vitamin D, innate activation of T cells and nephritis. We propose that lymphocyte shedding could account for the enhancement of sMICA and reflect an immune evasion mechanism driving disease activation in lupus.

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

Cited by 34 publications

References 56 publications

The NKG2D/NKG2DL Axis in the Crosstalk Between Lymphoid and Myeloid Cells in Health and Disease

The NKG2D/NKG2DL Axis in the Crosstalk Between Lymphoid and Myeloid Cells in Health and Disease

More than Decoration: Roles for Natural Killer Group 2 Member D Ligand Expression by Immune Cells

A subgroup of lupus patients with nephritis, innate T cell activation and low vitamin D is identified by the enhancement of circulating MHC class I-related chain A

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