Inhibitory and Coactivating Receptors Recognising the Same Ligand: Immune Homeostasis Exploited by Pathogens and Tumours

Levi‐Schaffer, Francesca; Mandelboim, Ofer

doi:10.1016/j.it.2017.10.001

Cited by 20 publications

(18 citation statements)

References 73 publications

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“…However, their effect on NK cells is complex as the same ligand (e.g. CD155, nectin-2) can both activate and inhibit NK cells though competing interaction with paired receptors CD226 and TIGIT [78]. The role of CD96 itself is less well defined and appears ambivalent as it has been shown to be an activator of human NK cells but an inhibitor of murine NK cells [24].…”

Section: Discussionmentioning

confidence: 99%

“…Since the hCD96 isoform 2 that we used here has a relatively low affinity for nectin-1, we did not test the rarer isoform 1, which presumably would bind with an even lower affinity. The interaction between human nectin-1 and hCD96 in vitro has a relatively low affinity compared to other interactions between nectins and NK cell Ig receptors (summarized in [1, 78]). The 2.4 μM affinity constant (K D ) measured here is larger than the K D of many nectin homophilic trans-interactions [1], suggesting that, on its own, CD96 may not interact with nectin-1 molecules already engaged in trans-interactions at cell junctions.…”

Section: Discussionmentioning

confidence: 99%

“…However, the levels of CD155 in K562-N1G cells has not been measured. Overall, the affinity between various nectins and cognate NK cell receptors likely contributes to the regulation of NK cell activity, especially in a complex system where activating and inhibitory receptors share ligands on target cells [26, 78].…”

Section: Discussionmentioning

confidence: 99%

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Interaction between nectin-1 and the human natural killer cell receptor CD96

et al. 2019

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Regulation of Natural Killer (NK) cell activity is achieved by the integration of both activating and inhibitory signals acquired at the immunological synapse with potential target cells. NK cells express paired receptors from the immunoglobulin family which share common ligands from the nectin family of adhesion molecules. The activating receptor CD226 (DNAM-1) binds to nectin-2 and CD155, which are also recognized by the inhibitory receptor TIGIT. The third receptor in this family is CD96, which is less well characterized and may have different functions in human and mouse models. Human CD96 interacts with CD155 and ligation of this receptor activates NK cells, while in mice the presence of CD96 correlates with decreased NK cell activation. Mouse CD96 also binds nectin-1, but the effect of this interaction has not yet been determined. Here we show that human nectin-1 directly interacts with CD96 in vitro . The binding site for CD96 is located on the nectin-1 V-domain, which comprises a canonical interface that is shared by nectins to promote cell adhesion. The affinity of nectin-1 for CD96 is lower than for other nectins such as nectin-3 and nectin-1 itself. However, the affinity of nectin-1 for CD96 is similar to its affinity for herpes simplex virus glycoprotein D (HSV gD), which binds the nectin-1 V-domain during virus entry. The affinity of human CD96 for nectin-1 is lower than for its known activating ligand CD155. We also found that human erythroleukemia K562 cells, which are commonly used as susceptible targets to assess NK cell cytotoxicity did not express nectin-1 on their surface and were resistant to HSV infection. When expressed in K562 cells, nectin-1-GFP accumulated at cell contacts and allowed HSV entry. Furthermore, overexpression of nectin-1-GFP led to an increased susceptibility of K562 cells to NK-92 cell cytotoxicity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Interaction between nectin-1 and the human natural killer cell receptor CD96

et al. 2019

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“…67 , 221 , 222 In the absence of infection, inhibitory HLA-KIR signals dominate and protect tumor cells from NK cell-mediated lysis, while intracytoplasmic binding of KIR2DL or KIR3DL with ITIMs prevent NK cell lysis activity. 68 , 223 Conversely, KIR2DS and KIR3DS are noncovalently associated with an ITAM–bearing adapter molecule DAP-12, which results in phosphorylation of tyrosine residue in the ITAM and recruiting ZAP-70 or Syk, leading to cellular activation and increases the capacity of NK cells to recognize tumor cells; this is an essential target for cancer treatment. 26 , 224 , 225 KIR has been established to play a critical role in mediating self-tolerance along with the facilitation of cytotoxicity against infected cells and transformed cells.…”

Section: Nk Cell As a Promising Therapeutic Target For Cancermentioning

confidence: 99%

Immune checkpoint molecules in natural killer cells as potential targets for cancer immunotherapy

Cao

Wang

Jin

et al. 2020

Sig Transduct Target Ther

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Recent studies have demonstrated the potential of natural killer (NK) cells in immunotherapy to treat multiple types of cancer. NK cells are innate lymphoid cells that play essential roles in tumor surveillance and control that efficiently kill the tumor and do not require the major histocompatibility complex. The discovery of the NK’s potential as a promising therapeutic target for cancer is a relief to oncologists as they face the challenge of increased chemo-resistant cancers. NK cells show great potential against solid and hematologic tumors and have progressively shown promise as a therapeutic target for cancer immunotherapy. The effector role of these cells is reliant on the balance of inhibitory and activating signals. Understanding the role of various immune checkpoint molecules in the exhaustion and impairment of NK cells when their inhibitory receptors are excessively expressed is particularly important in cancer immunotherapy studies and clinical implementation. Emerging immune checkpoint receptors and molecules have been found to mediate NK cell dysfunction in the tumor microenvironment; this has brought up the need to explore further additional NK cell-related immune checkpoints that may be exploited to enhance the immune response to refractory cancers. Accordingly, this review will focus on the recent findings concerning the roles of immune checkpoint molecules and receptors in the regulation of NK cell function, as well as their potential application in tumor immunotherapy.

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“…An appropriate regulation of the immune system is dependent, among other factors, on a delicate balance between activating and inhibitory signals transmitted by a variety of receptors found on the surface of immune cells . The CD300 receptors are type I transmembrane proteins expressed in both myeloid and lymphoid lineages and modulate immune responses by their stimulatory and inhibitory capabilities.…”

Section: Introductionmentioning

confidence: 99%

CD300 receptor family in viral infections

et al. 2018

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The CD300 molecules constitute an evolutionarily significant family of receptors that are expressed on myeloid and lymphoid cells, but also on other cell types, such as tuft cells. Many of the CD300 receptors have been shown to recognize lipids, e.g. phosphatidylserine and phosphatidylethanolamine. Over the past couple of years, accumulating evidence has shown that this family of receptors is involved in the pathogenesis of many diseases. Specifically, CD300 molecules participate in the mechanisms that viruses employ to develop immune evasion strategies and to infect host cells. The participation of CD300 molecules in viral infection includes both lipid dependent and independent mechanisms, as for example in infections with dengue virus (DENV) and murine norovirus (MNV), respectively. CD300 receptors are also involved in viral escape mechanisms, for instance inhibiting NK cell‐mediated cytotoxicity against infected cells. Moreover, it is becoming increasingly recognized that the expression of CD300 receptors is altered during viral diseases. Here, we review the involvement of human and murine CD300 molecules in viral binding and entry and in cellular responses to viruses, which highlights the potential of CD300 molecules in the search of new biomarkers for various stages of infection and therapeutic targets for the treatment of viral infections.

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Inhibitory and Coactivating Receptors Recognising the Same Ligand: Immune Homeostasis Exploited by Pathogens and Tumours

Cited by 20 publications

References 73 publications

Interaction between nectin-1 and the human natural killer cell receptor CD96

Interaction between nectin-1 and the human natural killer cell receptor CD96

Immune checkpoint molecules in natural killer cells as potential targets for cancer immunotherapy

CD300 receptor family in viral infections

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