The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions

Chan, Christopher J.; Martinet, Ludovic; Gilfillan, Susan; Souza-Fonseca-Guimarães, Fernando; Chow, Melvyn T.; Town, Liam; Ritchie, David; Colonna, Marco; Andrews, Daniel M.; Smyth, Mark J.

doi:10.1038/ni.2850

Cited by 404 publications

(464 citation statements)

References 41 publications

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“…CD226 was originally described as an adhesion coreceptor stimulating NK cell-and CD8 + T cell-mediated cytotoxicity against tumor cells (19). It has now become clear that this receptor has broader implications than originally thought in controlling NK cell and T cell function (20,21). CD226 has been implicated in immunological synapse formation (22), T cell proliferation and differentiation (23), and cytokine secretion (21,24).…”

Section: Introductionmentioning

confidence: 99%

“…It has now become clear that this receptor has broader implications than originally thought in controlling NK cell and T cell function (20,21). CD226 has been implicated in immunological synapse formation (22), T cell proliferation and differentiation (23), and cytokine secretion (21,24). Interestingly, CD112 and CD155 are often present at the surface of malignant PCs in MM patients, and CD226 strongly contributes to NK cell-mediated killing of MM cells in vitro (8,9).…”

Section: Introductionmentioning

confidence: 99%

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Immunosurveillance and therapy of multiple myeloma are CD226 dependent

Guillerey¹,

Andrade²,

Vučković³

et al. 2015

J. Clin. Invest.

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113

114

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immunosurveillance and therapy of multiple myeloma are CD226 dependent

Guillerey¹,

Andrade²,

Vučković³

et al. 2015

J. Clin. Invest.

Self Cite

113

114

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“…30 Table 2 illustrates more examples of differentially methylated genes from other activated immune cells that appear to be common with NK cell activation. [30][31][32][33][34][35][36][37][38][39] The Th2 cytokine locus has been intensively studied as a model of chromatin dynamics directing gene expression in the immune system. The genes encoding the Th2 cytokines IL4, IL5 and IL13 are clustered in a 160 kb region of chromosome 5q31 in humans.…”

Section: 914mentioning

confidence: 99%

The DNA methylation profile of activated human natural killer cells

et al. 2016

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Natural killer (NK) cells are now recognized to exhibit characteristics akin to cells of the adaptive immune system. The generation of adaptive memory is linked to epigenetic reprogramming including alterations in DNA methylation. The study herein found reproducible genome wide DNA methylation changes associated with human NK cell activation. Activation led predominately to CpG hypomethylation (81% of significant loci). Bioinformatics analysis confirmed that non-coding and gene-associated differentially methylated sites (DMS) are enriched for immune related functions (i.e., immune cell activation). Known DNA methylation-regulated immune loci were also identified in activated NK cells (e.g., TNFA, LTA, IL13, CSF2). Twenty-one loci were designated high priority and further investigated as potential markers of NK activation. BHLHE40 was identified as a viable candidate for which a droplet digital PCR assay for demethylation was developed. The assay revealed high demethylation in activated NK cells and low demethylation in na€ ıve NK, T-and B-cells. We conclude the NK cell methylome is plastic with potential for remodeling. The differentially methylated region signature of activated NKs revealed similarities with T cell activation, but also provided unique biomarker candidates of NK activation, which could be useful in epigenome-wide association studies to interrogate the role of NK subtypes in global methylation changes associated with exposures and/or disease states.

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“…TIGIT has been found to limit autoimmunity (2,7) and to restrain T cell responses acting as an intrinsic inhibitory molecule by decreasing TCR activation, proliferation, and cytokine secretion (5,7). TIGIT expressed on T or NK cells can bind to its high-affinity ligand CD155 (1), also known as poliovirus receptor (8) or Necl-5 (9), expressed on the surface of APCs (4,10,11). Engagement of TIGIT to CD155 promotes IL-10 while it restrains IL-12 production by dendritic cells (DCs), leading to reduced T cell activation in vitro (4).…”

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confidence: 99%

TIGIT Enhances Antigen-Specific Th2 Recall Responses and Allergic Disease

Kourepini

Paschalidis

Simoes

et al. 2016

The Journal of Immunology

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T cell Ig and ITIM domain receptor (TIGIT), expressed on T, NK, and regulatory T cells, is known as an inhibitory molecule that limits autoimmunity, antiviral and antitumor immunity. In this report, we demonstrate that TIGIT enhances Th2 immunity. TIGIT expression was upregulated in activated Th2 cells from mice with experimental allergic disease and in Th2 polarization cultures. In addition, its high-affinity ligand CD155 was upregulated in mediastinal lymph node dendritic cells from allergic mice. In an in vitro setting, we observed that Tigit expression in Th2 cells and its interaction with CD155 expressed in dendritic cells were important during the development of Th2 responses. In addition, blockade of TIGIT inhibited Th2, but had no effect on either Th1 or Th17 polarization. In vivo blockade of TIGIT suppressed hallmarks of allergic airway disease, such as lung eosinophilia, goblet cell hyperplasia, Ag-specific Th2 responses, and IgE production, and reduced numbers of T follicular helper and effector Th2 cells. Thus, TIGIT is critical for Th2 immunity and can be used as a therapeutic target, especially in light of recent findings showing TIGIT locus hypomethylation in T cells from pediatric patients with allergic asthma.

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The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions

Cited by 404 publications

References 41 publications

Immunosurveillance and therapy of multiple myeloma are CD226 dependent

Immunosurveillance and therapy of multiple myeloma are CD226 dependent

The DNA methylation profile of activated human natural killer cells

TIGIT Enhances Antigen-Specific Th2 Recall Responses and Allergic Disease

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