Differential contribution of education through KIR2DL1, KIR2DL3, and KIR3DL1 to antibody-dependent (AD) NK cell activation and ADCC

Lisovsky, Irene; Kant, Sanket; Tremblay‐McLean, Alexandra; Isitman, Gamze; Kiani, Zahra; Dupuy, Franck P.; Gilbert, Louise; Bruneau, Julie; Shoukry, Naglaa H.; Lebouché, Bertrand; Bernard, Nicole F.

doi:10.1002/jlb.4a0617-242rrr

Cited by 13 publications

(14 citation statements)

References 66 publications

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“…Our results suggest that not only do KIR3DL1 ϩ cells respond to autologous HIV-infected cells but that KIR2DL1 ϩ , -L2 ϩ , and -L3 ϩ NK cells do so as well. It is worth noting that each of the spiKIR populations we worked with represents a small subset of the total NK cell population, on the order of Ͻ5% of NK cells (34,61). Although NK cell populations other than spiKIRs likely also contribute to HIV control, investigation of the responses of spiKIRs to autologous iCD4 cells is useful for dissecting the roles of NK cell education and HLA downmodulation by HIV Nef in the activation of these cells for antiviral activity.…”

Section: Discussionmentioning

confidence: 99%

The Education of NK Cells Determines Their Responsiveness to Autologous HIV-Infected CD4 T Cells

Kiani

Dupuy

Bruneau

et al. 2019

J Virol

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Several studies support a role for specific killer immunoglobulin-like receptor (KIR)–HLA combinations in protection from HIV infection and slower progression to AIDS. Natural killer (NK) cells acquire effector functions through education, a process that requires the interaction of inhibitory NK cell receptors with their major histocompatibility complex (MHC) class I (or HLA class I [HLA-I]) ligands. HLA-C allotypes are ligands for the inhibitory KIRs (iKIRs) KIR2DL1, KIR2DL2, and KIR2DL3, whereas the ligand for KIR3DL1 is HLA-Bw4. HIV infection reduces the expression of HLA-A, -B, and -C on the surfaces of infected CD4 (iCD4) T cells. Here we investigated whether education through iKIR-HLA interactions influenced NK cell responses to autologous iCD4 cells. Enriched NK cells were stimulated with autologous iCD4 cells or with uninfected CD4 cells as controls. The capacities of single-positive (sp) KIR2DL1, KIR2DL2, KIR2DL3, and KIR3DL1 NK cells to produce CCL4, gamma interferon (IFN-γ), and/or CD107a were assessed by flow cytometry. Overall, we observed that the potency of NK cell education was directly related to the frequency of each spiKIR+ NK cell’s ability to respond to the reduction of its cognate HLA ligand on autologous iCD4 cells, as measured by the frequency of production by spiKIR+ NK cells of CCL4, IFN-γ, and/or CD107a. Both NK cell education and HIV-mediated changes in HLA expression influenced NK cell responses to iCD4 cells. IMPORTANCE Epidemiological studies show that natural killer (NK) cells have anti-HIV activity: they are able to reduce the risk of HIV infection and/or slow HIV disease progression. How NK cells contribute to these outcomes is not fully characterized. We used primary NK cells and autologous HIV-infected cells to examine the role of education through four inhibitory killer immunoglobulin-like receptors (iKIRs) from persons with HLA types that are able to educate NK cells bearing one of these iKIRs. HIV-infected cells activated NK cells through missing-self mechanisms due to the downmodulation of cell surface HLA expression mediated by HIV Nef and Vpu. A higher frequency of educated than uneducated NK cells expressing each of these iKIRs responded to autologous HIV-infected cells by producing CCL4, IFN-γ, and CD107a. Since NK cells were from non-HIV-infected individuals, they model the consequences of healthy NK cell–HIV-infected cell interactions occurring in the HIV eclipse phase, when new infections are susceptible to extinction.

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Section: Discussionmentioning

confidence: 99%

The Education of NK Cells Determines Their Responsiveness to Autologous HIV-Infected CD4 T Cells

Kiani

Dupuy

Bruneau

et al. 2019

J Virol

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“…During the blood stage, KIR-expressing effector cells may respond more strongly to an HLA-devoid cell due to the loss of tonic inhibitory signaling via inhibitory KIR (43). KIR inhibition may also influence the clearance of parasites through ADCC (44,45). At either stage of infection, the observed genotypic differences in parasite prevalence may be mediated by NK cells, gd T cells or CD8 T cells, all of which can express KIR.…”

Section: Resultsmentioning

confidence: 99%

“…During the blood stage, KIR-expressing effector cells may respond more strongly to an HLA-devoid cell due to the loss of tonic inhibitory signaling via inhibitory KIR (Kim et al, 2008). KIR inhibition may also influence the clearance of parasites through antibody dependent cellular cytotoxicity (ADCC) (Lisovsky et al, 2019; Parsons et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Inhibitory KIR ligands are associated with higherP. falciparumparasite prevalence

Digitale

Callaway

Martin

et al. 2020

Preprint

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Killer cell immunoglobulin-like receptors (KIR) and their HLA ligands influence the outcome of many infectious diseases. Data from a longitudinal cohort comprised of three study sites in Uganda with varying malaria transmission intensity show that presence of the HLA-C2 and HLA-Bw4 ligands for inhibitory KIR2DL1 and KIR3DL1, respectively, increase the likelihood of Plasmodium falciparum (Pf) parasitemia in an additive manner. For KIR2DL1/2/3, parasite prevalence was highest among individuals with KIR/HLA-C ligand pairs that are capable of the greatest cellular inhibition. Individuals homozygous for HLA-C2, which mediates strong inhibition via the near ubiquitous KIR2DL1 receptor, had the highest odds of parasitemia, while HLAC1/C2 heterozygotes had intermediate odds, and individuals homozygous for HLA-C1, which mediates weaker inhibition through KIR2DL2/3, had the lowest odds of parasitemia. A higher risk of parasitemia was also observed in the pairing of HLA-C1 with its receptor KIR2DL2 compared to its less inhibitory receptor KIR2DL3. Additionally, higher surface expression of HLA-C, the ligand for KIR2DL1/2/3, was associated with a higher likelihood of parasitemia. Together these data indicate that stronger KIR-mediated inhibition confers a higher risk of Pf parasitemia and suggest that KIR-expressing effector cells play a role in mediating anti-parasite immunity.

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“…Thus, ADCC mediated by NK cells is presumed to be a key effector function [139]. However, NK cell education does not in luence ADCC levels, but does contribute to antibody-dependent NK cell activation [140]. NK cells harbor the activating differentiation molecule FcγRIIIa, which is also known as CD16a or CD32c, on their cell surfaces.…”

Section: Antitumor Eff Ects Of Nk Cellsmentioning

confidence: 99%

Natural killer cells in patients with hematologic malignancies, solid tumors and in recipients of hematopoietic stem cell transplantation

Ka¹,

Al-Jasser²,

Wk³

2019

J Stem Cell Ther Transplant

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Differential contribution of education through KIR2DL1, KIR2DL3, and KIR3DL1 to antibody-dependent (AD) NK cell activation and ADCC

Cited by 13 publications

References 66 publications

The Education of NK Cells Determines Their Responsiveness to Autologous HIV-Infected CD4 T Cells

The Education of NK Cells Determines Their Responsiveness to Autologous HIV-Infected CD4 T Cells

Inhibitory KIR ligands are associated with higherP. falciparumparasite prevalence

Natural killer cells in patients with hematologic malignancies, solid tumors and in recipients of hematopoietic stem cell transplantation

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