A Conserved HIV-1-Derived Peptide Presented by HLA-E Renders Infected T-cells Highly Susceptible to Attack by NKG2A/CD94-Bearing Natural Killer Cells

Davis, Zachary; Cogswell, Andrew; Scott, Hamish W; Mertsching, Amanda; Boucau, Julie; Wambua, Daniel; Gall, Sylvie Le; Planelles, Vicente; Campbell, Kerry S.; Barker, Edward

doi:10.1371/journal.ppat.1005421

Cited by 60 publications

(82 citation statements)

References 55 publications

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“…The primary focus in studies evaluating the role of inhibitory receptor on NK cell response to HIV-infected cells is on iNKR responses to MHC class I molecules. 20,28,[33][34][35][36] Since some KIRs may not be engaged due to modulation of HLA-A and -B by Nef 33,37 or the inability of HLA-E to trigger the iNKR NKG2A/CD94 28 and as we show in this study, HIV does not modulate CD155 on CD4 + T cells, it is likely that TIGIT may contribute to modulating NK cell response to HIV-infected cells.…”

Section: Fig 2 Nk Cells Lyse Autologous Hiv-infected T Cells When Dmentioning

confidence: 65%

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CD155 on HIV-Infected Cells Is Not Modulated by HIV-1 Vpu and Nef but Synergizes with NKG2D Ligands to Trigger NK Cell Lysis of Autologous Primary HIV-Infected Cells

Davis

Sowrirajan

Cogswell

et al. 2017

AIDS Research and Human Retroviruses

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Activation of primary CD4+ T cells induces the CD155, but not the CD112 ligands for the natural killer (NK) cell activation receptor (aNKR) CD226 [DNAX accessory molecule-1 (DNAM-1)]. We hypothesize that HIV productively infects activated CD4+ T cells and makes itself vulnerable to NK cell-mediated lysis when CD155 on infected T cells engages DNAM-1. The primary objective of this study is to determine whether CD155 alone or together with NKG2D ligands triggers autologous NK cell lysis of HIV-infected T cells and whether HIV modulates CD155. To determine whether HIV modulates this activation ligand, we infected ''activated'' CD4 + T cells with HIV in the absence or presence of Nef and/or Vpu and determined by flow cytometry whether they modulated CD155. To determine if CD155 alone, or together with NKG2D ligands, triggered NK cell lysis of autologous HIV-infected T cells, we treated purified NK cells with DNAM-1 and/or NKG2D blocking antibodies before the addition of purified autologous HIV-infected cells in cytolytic assays. Finally, we determined whether DNAM-1 works together with NKG2D as an NK cell coactivation receptor (caNKR) or whether they work independently as aNKRs to induce an NK cell lytic response. We demonstrate that HIV and specifically Nef and/or Vpu do not modulate CD155 on infected primary T cells; and both CD155 and NKG2D ligands synergize as aNKRs to trigger NK cell lysis of the infected cell.

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Section: Fig 2 Nk Cells Lyse Autologous Hiv-infected T Cells When Dmentioning

confidence: 65%

“…However, we noted that HLA-E on HIV-infected cells is unable to inhibit NK cell lysis. 28 Thus, while NK cells have the capacity to kill HIV-infected cells when triggered by CD155, HIV-1s downmodulation of NTB-A dampens the synergistic signal critical for DNAM-1-induced NK cell degranulation.…”

Section: Fig 2 Nk Cells Lyse Autologous Hiv-infected T Cells When Dmentioning

confidence: 99%

CD155 on HIV-Infected Cells Is Not Modulated by HIV-1 Vpu and Nef but Synergizes with NKG2D Ligands to Trigger NK Cell Lysis of Autologous Primary HIV-Infected Cells

Davis

Sowrirajan

Cogswell

et al. 2017

AIDS Research and Human Retroviruses

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“…The role of the inhibitory receptor NKG2A in NK cell responses to EBV remains unclear. NKG2A + NK cells are also enriched in the ability to respond to HIV (45). This observation is explained by the presentation of a conserved HIV peptide by HLA-E that abrogates the interaction between NKG2A and HLA-E, resulting in the loss of this inhibitory signal and sensitization to killing by NKG2A + NK cells (45).…”

Section: Discussionmentioning

confidence: 99%

“…NKG2A + NK cells are also enriched in the ability to respond to HIV (45). This observation is explained by the presentation of a conserved HIV peptide by HLA-E that abrogates the interaction between NKG2A and HLA-E, resulting in the loss of this inhibitory signal and sensitization to killing by NKG2A + NK cells (45). A similar mechanism could play a role in EBV, particularly since HLA-E is not downregulated by either HIV or EBV (46).…”

Section: Discussionmentioning

confidence: 99%

NKG2A-Expressing Natural Killer Cells Dominate the Response to Autologous Lymphoblastoid Cells Infected with Epstein–Barr Virus

et al. 2016

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Epstein–Barr virus (EBV) is a human γ-herpesvirus that establishes latency and lifelong infection in host B cells while achieving a balance with the host immune response. When the immune system is perturbed through immunosuppression or immunodeficiency, however, these latently infected B cells can give rise to aggressive B cell lymphomas. Natural killer (NK) cells are regarded as critical in the early immune response to viral infection, but their role in controlling expansion of infected B cells is not understood. Here, we report that NK cells from healthy human donors display increased killing of autologous B lymphoblastoid cell lines (LCLs) harboring latent EBV compared to primary B cells. Coculture of NK cells with autologous EBV+ LCL identifies an NK cell population that produces IFNγ and mobilizes the cytotoxic granule protein CD107a. Multi-parameter flow cytometry and Boolean analysis reveal that these functional cells are enriched for expression of the NK cell receptor NKG2A. Further, NKG2A+ NK cells more efficiently lyse autologous LCL than do NKG2A− NK cells. More specifically, NKG2A+2B4+CD16−CD57−NKG2C−NKG2D+ cells constitute the predominant NK cell population that responds to latently infected autologous EBV+ B cells. Thus, a subset of NK cells is enhanced for the ability to recognize and eliminate autologous, EBV-infected transformed cells, laying the groundwork for harnessing this subset for therapeutic use in EBV+ malignancies.

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“…Sequence polymorphisms within regions of HIV-1 that are targeted by inhibitory KIRs improved the binding and resulted in decreased antiviral activity of NK cells [62, 63]. In contrast, HIV sequence mutations can also prevent binding of inhibitory receptors to HLA molecules, thereby increasing the susceptibility of infected cells to lysis [64]. …”

Section: Counter-regulation Of the Nk Cell Response By Retrovirusesmentioning

confidence: 99%

Insufficient natural killer cell responses against retroviruses: how to improve NK cell killing of retrovirus-infected cells

2016

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Natural killer (NK) cells belong to the innate immune system and protect against cancers and a variety of viruses including retroviruses by killing transformed or infected cells. They express activating and inhibitory receptors on their cell surface and often become activated after recognizing virus-infected cells. They have diverse antiviral effector functions like the release of cytotoxic granules, cytokine production and antibody dependent cellular cytotoxicity. The importance of NK cell activity in retroviral infections became evident due to the discovery of several viral strategies to escape recognition and elimination by NK cells. Mutational sequence polymorphisms as well as modulation of surface receptors and their ligands are mechanisms of the human immunodeficiency virus-1 to evade NK cell-mediated immune pressure. In Friend retrovirus infected mice the virus can manipulate molecular or cellular immune factors that in turn suppress the NK cell response. In this model NK cells lack cytokines for optimal activation and can be functionally suppressed by regulatory T cells. However, these inhibitory pathways can be overcome therapeutically to achieve full activation of NK cell responses and ultimately control dissemination of retroviral infection. One effective approach is to modulate the crosstalk between NK cells and dendritic cells, which produce NK cell-stimulating cytokines like type I interferons (IFN), IL-12, IL-15, and IL-18 upon retrovirus sensing or infection. Therapeutic administration of IFNα directly increases NK cell killing of retrovirus-infected cells. In addition, IL-2/anti-IL-2 complexes that direct IL-2 to NK cells have been shown to significantly improve control of retroviral infection by NK cells in vivo. In this review, we describe novel approaches to improve NK cell effector functions in retroviral infections. Immunotherapies that target NK cells of patients suffering from viral infections might be a promising treatment option for the future.

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A Conserved HIV-1-Derived Peptide Presented by HLA-E Renders Infected T-cells Highly Susceptible to Attack by NKG2A/CD94-Bearing Natural Killer Cells

Cited by 60 publications

References 55 publications

CD155 on HIV-Infected Cells Is Not Modulated by HIV-1 Vpu and Nef but Synergizes with NKG2D Ligands to Trigger NK Cell Lysis of Autologous Primary HIV-Infected Cells

CD155 on HIV-Infected Cells Is Not Modulated by HIV-1 Vpu and Nef but Synergizes with NKG2D Ligands to Trigger NK Cell Lysis of Autologous Primary HIV-Infected Cells

NKG2A-Expressing Natural Killer Cells Dominate the Response to Autologous Lymphoblastoid Cells Infected with Epstein–Barr Virus

Insufficient natural killer cell responses against retroviruses: how to improve NK cell killing of retrovirus-infected cells

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