Functional advantage of educated KIR2DL1+ natural killer cells for anti-HIV-1 antibody-dependent activation

Abstract

Summary Evidence from the RV144 HIV‐1 vaccine trial implicates anti‐HIV‐1 antibody‐dependent cellular cytotoxicity (ADCC) in vaccine‐conferred protection from infection. Among effector cells that mediate ADCC are natural killer (NK) cells. The ability of NK cells to be activated in an antibody‐dependent manner is reliant upon several factors. In general, NK cell‐mediated antibody‐dependent activation is most robust in terminally differentiated CD57+ NK cells, as well as NK cells educated through ontological interactions between inhibitory killer immunoglobulin‐like receptors (KIR) and their major histocompatibility complex class I [MHC‐I or human leucocyte antigen (HLA‐I)] ligands. With regard to anti‐HIV‐1 antibody‐dependent NK cell activation, previous research has demonstrated that the epidemiologically relevant KIR3DL1/HLA‐Bw4 receptor/ligand combination confers enhanced activation potential. In the present study we assessed the ability of the KIR2DL1/HLA–C2 receptor/ligand combination to confer enhanced activation upon direct stimulation with HLA‐I‐devoid target cells or antibody‐dependent stimulation with HIV‐1 gp140‐pulsed CEM.NKr‐CCR5 target cells in the presence of an anti‐HIV‐1 antibody source. Among donors carrying the HLA‐C2 ligand for KIR2DL1, higher interferon (IFN)‐γ production was observed within KIR2DL1+ NK cells than in KIR2DL1– NK cells upon both direct and antibody‐dependent stimulation. No differences in KIR2DL1+ and KIR2DL1– NK cell activation were observed in HLA‐C1 homozygous donors. Additionally, higher activation in KIR2DL1+ than KIR2DL1– NK cells from HLA–C2 carrying donors was observed within less differentiated CD57– NK cells, demonstrating that the observed differences were due to education and not an overabundance of KIR2DL1+ NK cells within differentiated CD57+ NK cells. These observations are relevant for understanding the regulation of anti‐HIV‐1 antibody‐dependent NK cell responses.

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

“…The advantage of NK cells educated through 3DL1 and 2DL1 compared to their uneducated counterparts in responding to ADNKA has been reported by others . However, the previously reported observations were made using an inclusive gating strategy that would not have excluded NK cells co‐expressing NKG2A or other nonstained for iKIR on 3DL1 + and 2DL1 + NK cells.…”

“…32 The advantage of NK cells educated through 3DL1 and 2DL1 compared to their uneducated counterparts in responding to ADNKA has been reported by others. [59][60][61][62] However, the previously reported observations were made using an inclusive gating strategy that would not have excluded NK cells co-expressing NKG2A or other nonstained for iKIR on 3DL1 + and 2DL1 + NK cells. The exclusive gating strategy used here detects a more restricted population of NK cells, in which the influence of NKG2A, and several other iKIR on responsiveness to HIVIG Ab opsonized gp120-coated CEM cells is minimized.…”

Phenotypic and Functional Characterization of Circulatory, Splenic, and Hepatic NK Cells in Simian Immunodeficiency Virus–Controlling Macaques

“…Given the recent evidence that NK cells can develop long-term memory-like functional responses (10, 24–26), and that these antigen-specific NK cell responses in humans are associated with expression of CD57 and the lack of the intracellular adaptor protein, FcεRIγ (27–30), we evaluated CD57 and FcεRIγ expression in circulatory and splenic NK cells. Similar to humans, FcεRIγ-deficient NK cells in rhesus macaques were detectable at variable rates (Fig.…”

Vaccinating for natural killer cell effector functions

“…Indeed, RV144 induced isotypes IgG1 and IgG3 targeting the crown of the V2 loop demonstrating the potential for NK cell ADCC induction . NK cells from KIR3DL1/HLA‐Bw4 + or KIR2DL1/HLA‐C2 + donors show higher cytotoxicity against HIV‐infected targets in the presence of anti‐HIV gp120 antibody, highlighting the influence of NK cell education to HIV vaccine‐induced effector NK cells and potentially contributing to individual variability in vaccine outcomes . CD57 + NKG2C + memory‐like NK cells are expanded in HIV‐1/HCMV co‐infected individuals, and these cells make a potential contribution to control of viremia during primary HIV infection .…”

“…70,71 NK cells from KIR3DL1/HLA-Bw4 + or KIR2DL1/HLA-C2 + donors show higher cytotoxicity against HIV-infected targets in the presence of anti-HIV gp120 antibody, highlighting the influence of NK cell education to HIV vaccineinduced effector NK cells and potentially contributing to individual variability in vaccine outcomes. 72,73 CD57 + NKG2C + memory-like NK cells are expanded in HIV-1/HCMV co-infected individuals, and these cells make a potential contribution to control of viremia during primary HIV infection. 74,75 Together with evidence that individuals with a degree of inherent resistance to HIVso-called elite controllers or slow progressorsmount stronger antibody-mediated NK cell activation and ADCC responses than more susceptible individuals, these studies suggest that NK cells may contribute to HIV protection and control.…”