Altered dendritic cell–natural killer interaction in Kenyan sex workers resistant to HIV-1 infection
Ghadially, Hormasa,b; Keynan, Yoavc,d; Kimani, Joshuac,d; Kimani, Makobud; Ball, T. Blakec,d,e; Plummer, Francis A.c,d,f; Mandelboim, Ofera; Meyers, Adrienne F.A.c,d,e
aThe Lautenberg Center for General and Tumor Immunology, The Hebrew University Hadassah Medical School, Jerusalem, Israel
bMedImmune Limited, Granta Park, Cambridge, UK
cDepartment of Medical Microbiology, University of Manitoba, Winnipeg, Canada
dDepartment of Medical Microbiology, University of Nairobi, Nairobi, Kenya
eNational HIV and Retrovirology Laboratories
fNational Microbiology Lab, Public Health Agency of Canada, Winnipeg, Canada.
Correspondence to Adrienne Meyers, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg MB R3E 3R2, Canada. E-mail: Adrienne.Meyers@phac-aspc.gc.ca
Received 10 August, 2011
Revised 31 October, 2011
Accepted 23 November, 2011
Background: Natural killer (NK) cells are members of the innate immune system that play an important role in the defense against viral infection. They are also involved in the regulation of adaptive immune responses through cytokine secretion and the interaction with antigen-presenting cells. However, their role in HIV infection is only partially understood.
Objective: Here we studied the phenotype and function of NK cells of highly HIV-exposed but seronegative (HESN) uninfected commercial sex workers from Kenya who can be epidemiologically defined as relatively resistant to HIV infection.
Design: The purpose of this study was to gain insight into the role of NK cells in mediating resistance to HIV-1. This information can be used to better understand protection from infection which can be used for informing future design of effective prophylactics and therapeutics for HIV.
Methods: Whole blood samples were collected from study participants and isolated NK cells and dendritic cells were used in assays for phenotyping and cell function.
Results: Activated NK cells from resistant women killed autologous immature dendritic cells more efficiently and also secreted more interferon (IFN)-γ than those of uninfected, susceptible women. Interestingly, NK cells from HIV-resistant women were significantly more effective in inducing secretion of IL-12 in immature dendritic cells.
Conclusions: These data suggest that an altered NK cell–dendritic cell interaction plays an important role in the protection from infection with HIV-1.
Natural killer (NK) cells are lymphocytes of the innate immune system and have been recognized to play an important role in the defense against virally infected or transformed cells, independently of prior antigen-specific activation . Unlike T or B lymphocytes, the activity of NK cells is regulated by complex interactions of germ-line encoded activating and inhibitory receptors . Inhibitory NK receptors primarily bind to major histocompatibility complex (MHC) class I proteins, thereby detecting the absence of MHC class I due to infection or transformation (‘missing-self’ hypothesis ).
Activating NK receptors (like NKG2D) also recognize either MHC class I molecules or MHC class I-related proteins such as the stress-induced ligands . In contrast, some activating receptors bind directly to pathogen-derived molecules; examples include the murine Ly49H which binds to a viral MHC class I-related molecule m157 [5,6] or the human NKp44 and NKp46 receptors capable of recognizing viral haemaglutinins and NKp30 which binds to the cytomegalovirus (CMV) tegument protein pp65 [7–9]. NKp44 and NKp46 together with NKp30 are collectively called natural cytotoxicity receptors (NCRs); one member, NKp46, is uniquely expressed by NK cells .
The importance of NK cells in control of viral infection has been shown for many viruses. Direct cytotoxicity and interferon (IFN)-γ production has been shown to be crucial in herpes simplex virus (HSV)-1 , influenza , and CMV  infections and viral control is dependent on different subsets of NK cells and NK cell receptors.
Although the role of NK cells in HIV-1 infection is not clear, mounting evidence from several studies suggest an important role for NK cells in all phases of HIV-1 infection. Significant changes in NK cell populations in the peripheral circulation have been described, with dramatic reductions in the level of CD3neg CD56pos NK cells . Moreover, a functionally defective third subset of CD3neg CD56neg CD16pos NK cells, rare in healthy individuals, has been found in HIV-infected patients [15,16].
Several studies have also addressed the role of human leukocyte antigen (HLA) class I alleles and killer cell immunoglobulin-like receptor (KIR) alleles in HIV infection. Importantly, Martin et al. have shown that among individuals co-expressing KIR3DS1 and HLA-BW4 801 HIV disease progresses at a significantly slower rate and elevated transcripts of KIR3DS1 have been shown in highly HIV-1-exposed but persistently seronegative (HESN) intravenous drug users . Additionally, serum levels of soluble MHC class I chain-related protein A (MICA) have recently been shown to be elevated in chronic HIV infection, leading to NK cell dysfunction .
Natural killer cells are not only involved in the direct recognition of infected or HLA-deficient cells, but they are also involved in regulation of the adaptive immune response through interaction with other cells, most importantly dendritic cells. Human NK cells have been shown to be capable of inducing the maturation of dendritic cells, an effect mediated by tumour necrosis factor (TNF)-α and IFN-γ and triggered by engagement of NKp30 . This in turn stimulates production of interleukin (IL)-12 in dendritic cells which helps to shape the adaptive immune response.
Conversely, dendritic cells are also able to activate NK cells both in vitro and in vivo, a process that involves the presentation of IL-15 in trans by IL15Rα.
In-vitro activated human NK cells have been shown to kill immature monocyte-derived dendritic cells in an NKp30-dependent manner, whereas the involvement of NKp46 in this process remains controversial [23,24]. In contrast, mature dendritic cells are protected from killing, partly because of the up-regulation of MHC class I molecules during maturation .
Whereas the importance of dendritic cell–NK interaction in response to persistent viral infection with various viruses like CMV has been well studied [26–28], dendritic cell–NK interaction in HIV infection has only recently come into focus (reviewed in [29,30].
A recent study indicated that the interaction between NK cells and dendritic cells is affected by HIV infection, and that this interaction might be important for the control of virus replication. Mavilio et al. reported that the interactions of NK cells and in-vitro monocyte-derived dendritic cells (MoDCs) from viraemic HIV-1 patients are defective: Dendritic cells from HIV-infected individuals are not able to induce proliferation of NK cells as effectively as those from healthy individuals. Moreover, MoDCs from viraemic HIV-1 patients produced less IL-12 and were defective in inducing IFN-γ secretion from autologous NK cells. In addition, HIV-infected dendritic cells were shown to escape TNF-related apoptosis-inducing ligand (TRAIL)-mediated NK cell cytotoxicity by the up-regulation of two antiapoptotic molecules, the cellular-Flice like inhibitory protein (c-FLIP) and the cellular inhibitor of apoptosis 2 (c-IAP2) . Additionally, exposure of dendritic cells to HIV in vitro has been shown to induce IL-10 secretion and escape from lysis by NK cells .
These data illustrate the importance of the dendritic cell–NK axis during infection with HIV; however, it is unknown what role, if any, this axis plays in the prevention of HIV-1 infection in resistant individuals.
Cohorts of commercial sex workers who are persistently exposed to HIV yet remain uninfected are excellent models to study altered susceptibility to infection and the role of the immune system in this process . In this study, we investigated the NK cell population in the peripheral blood of individuals from the well characterized Pumwani cohort of female commercial sex workers in Nairobi, Kenya , in an effort to identify a possible role of activating receptors of NK cells in the protection from HIV infection. A number of the individuals in this cohort have remained uninfected with HIV despite intense, ongoing exposure to the virus. A subset of the cohort participants can be epidemiologically defined as relatively resistant to HIV infection – HIV-exposed, seronegative (HESN), remaining seronegative after 7 years of active sex work. These women are at extremely high risk for infection with HIV-1 with roughly 60% seroprevalence at time of enrollment into the cohort, and based upon HIV incidence we expect the majority of HIV-uninfected individuals to seroconvert by 7 years of follow-up. Resistance to HIV in this cohort is not due to polymorphisms in chemokine co-receptors for the virus, nor to alterations in cellular in-vitro susceptibility to infection .
In addition to the putative role of NK cell receptors in resistance, the role of the interaction of NK cells with dendritic cells was investigated in order to understand whether differences in the dendritic cell and NK cell interactions are involved in mediating protection from infection with HIV-1 in resistant individuals as compared with infected and noninfected individuals.
Written informed consent was obtained from all study participants. The study was approved by ethics review boards from the Universities of Manitoba and Nairobi.
Female commercial sex workers enrolled in the Pumwani Sex Worker Cohort in Nairobi, Kenya were study participants for the work described here. Each individual granted informed consent for their participation and this study was conducted in accordance with the ethical requirements from both the University of Nairobi and the University of Manitoba. Enrollment and follow-up practices have been described previously [37,38]. Study participants include the following three groups – HIV-resistant: these women have been enrolled in the cohort for a minimum of 7 years and remain uninfected with HIV despite ongoing, intense levels of exposure to the virus – also referred to as HESN; HIV-positive: more than 400 women active in our cohort are HIV-infected and at various stages of disease progression; HIV-negative: HIV-1-uninfected women who are active in sex work but have been enrolled in our cohort for less than 3 years . A small subset of the HIV-negative women will go on to become resistant, whereas the majority will become infected with HIV-1 despite active efforts at intervention. All participants in this study were clinically healthy at the time of the study with no evidence of clinical illness, including additional sexually transmitted infections and were age-matched for comparisons.
Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood samples provided by study participants of the Pumwani Sex Worker Cohort. Study participants included those highly exposed seronegative (HESN, ‘resistant’) for HIV, HIV infected (’positive’) and uninfected, susceptible (’negative’) individuals. Uninfected, susceptible controls were individuals from the same cohort, with similar high-risk exposure that have not met the criteria for resistance (enrolled in the cohort for less than 7 years).
For flow cytometry 1 × 106 PBMCs were washed twice with fluorescent activated cell sorter (FACS) buffer [PBS, 1% BSA (Sigma–Aldrich, Oakville, Ontario, Canada)] and were surface stained with 1 μl of the appropriate antibody in 100 μl of FACS buffer for 60 min at 4°C in the dark. Afterwards, cells were washed twice and either re-suspended in 200 μl of FACS buffer for analysis or permeabilized and fixed with the Cytofix/Cytoperm kit BD Biosciences (Franklin Lakes, New jersey, USA) according to the manufacturer's protocol.
For intracellular staining, 1 μl of the appropriate antibody in 100 μl of FACS buffer for 30 min at 4°C in the dark was used. If not stated otherwise, NK cells were defined as CD3neg CD56pos.
CD16 APC CY7 (clone 3G8), CD56 Alexa 700 (clone HCD56), CD69 Pac Blue (clone FN50), CD94 FITC (clone DX22), CD226 (DNAM-1) FITC (clone DX11), CD158a/h FITC (clone HP-MA4), NKG2D PE (clone 1D11), IL-15Ra PE (clone JM7A4), CD253 (TRAIL) PE (clone RIK-2), CD244 (2B4) APC (clone C1.7), CD337 (NKp30) APC (clone P30–15), CD336 (NKp44) APC (clone P44–8) and IFN-γ APC (clone 4S.B3) were all from Biolegend (San Diego, California, USA). CD3 AmCyan (clone SK7) and HLA-DR PeCy5 (clone G46–6) were from BD Biosciences. CD25 PeCy7 (clone BC96) and CD107a PeCy5 (clone eBioH4A3) were from eBiosciences (San Diego, California, USA). CD335 (NKp46) FITC (clone FC195314), NKG2C PE (clone 134591) and NKG2A APC (clone FC131411) were from R&D Systems (Minneapolis, Minnesota, USA). CD158b1/b2.j PE (clone GL183), CD85j PE (clone HP-F1), CD158i PE (clone FES172) and CD158e1/e2 PE (clone Z27.3.7) were from Beckman-Coulter (Brea, California, USA).
Cells were analysed using a BD LSR 2 flow cytometer (BD Biosciences).
The MHC class I negative NK target cell line K562 (American Type Culture Collection) were cultured in complete medium [Roswell Park Memorial Institute (RPMI), 10%FCS, 1% Gln, 1% Pen/Strep].
Natural killer cells were isolated from PBMCs with the NK cell isolation kit (Miltenyi Biotech, Bergisch Gladbach, Germany) according to the manufacturer's protocol. Isolated cells were above 95% CD56+ CD3−. 1 × 105 cells were cultured in a total volume of 100 μl in complete medium in the presence of 200 U/ml rhIL-2 (Roche, Madison, Wisconsin, USA) at 37°C, 5% CO2 for 6 days.
Dendritic cells were grown from CD14+ cells which had been isolated from PBMCs using anti-CD14 Microbeads (Miltenyi Biotech) according to the manufacturer's protocol. 1 × 105 cells were cultured in a total volume of 100 μl in complete medium in the presence of 200 U/ml rhIL-4 (PreproTech, Rocky Hill, New Jersey, USA) and 200 ng/ml hrGM-CSF (R&D Systems) for 6 days.
For dendritic cell–NK co-culture 1 × 104 dendritic cells were co-cultured in complete medium in the presence of 1 × 104 or 5 × 103 autologous NK cells in a total volume of 200 μl of in complete medium. After 48 h cells were washed in cold FACS buffer and stained with anti-CD3 and anti-CD56 and intracellular IFN-γ prior to flow cytometric analysis.
CD107a mobilization assay
After PMBCs had been washed twice in complete medium (RPMI, 10% FCS, 1% Gln, 1% Pen/Strep) 1 × 106 cells were incubated with 5 × 105 K562 cells as target cells (E/T ratio 2 : 1).
Alternatively, 1 × 104 dendritic cells were co-cultured in complete medium in the presence of 1 × 105 autologous rhL-2-activated NK cells (E/T ratio 10 : 1).
The cells were incubated for 3 h at 37°C in a total volume of 200 μl of in complete medium in the presence of 1 μl of conjugated anti-CD107a antibody and 1.4 μl GolgiStop (BD Biosciences). Afterwards, cells were washed twice in cold FACS buffer and stained with anti-CD3 and anti-CD56 prior to flow cytometric analysis.
IL-12 and IFN-γ in the supernatants of dendritic cell–NK co-cultures were measured using the human IL-12 (p70) and the human IFN-γ ELISA MAX Set Standard (Biolegend) according to the manufacturer's protocol and the TMB Substrate Reagent Set (Biolegend).
Statistical analysis of the experimental data was performed using a two-tailed Student's t test. A value of P less than 0.05 was considered statistically significant.
Results and discussion
Phenotypic characterization of natural killer cells in HIV-positive, negative, and resistant patients
In order to gain insight into the role that NK cells play in the protection from HIV-1 infection, PBMCs from HIV-infected, uninfected and resistant individuals were isolated and stained with a panel of antibodies directed mainly against activating NK receptors and markers for cell activation.
A summary is shown in Table 1. In general, variations between individuals within the study groups were often high. The percentages of CD3−, CD56+ NK cells expressing certain activating NK cell receptors like NKG2D, DNAM-1 appear to be lower in resistant than in HIV-negative individuals, whereas the number of NK cells which express NKp44 tended to be higher. While no statistically significant differences were observed between HIV-positive and HIV-negative or resistant individuals, a closer examination of highly viraemic individuals only may reveal some changes in expression of NK markers. However, no statistically significant differences between the groups were observed.
Additionally, CD107a mobilization assays were performed to investigate if NK cells derived from HESN had an improved ability to kill the NK-susceptible target cell line K562 (Fig. 1). While NK cells isolated from HIV-negative patients and from HESN appeared to degranulate more efficiently in response to K562 cells than those taken from HIV-infected participants, these differences did not reach statistical significance.
The interaction of dendritic cells and natural killer cells in HIV-positive, negative, and resistant patients
Mavilio et al. reported that in-vitro MoDCs from viraemic HIV-1 patients produced less IL-12 and were defective in inducing IFN-γ secretion by autologous NK cells. Moreover, immature dendritic cells (iDCs) from HIV-infected patients were shown to be relatively resistant to killing by autologous IL-2-activated NK cell . To test whether the interactions of dendritic cells and NK cells are altered in HESN individuals, MoDCs were cultured from CD14+ selected cells, in the presence of IL-4 and granulocyte macrophage–colony stimulating factor and NK cells were isolated from PBMCs and cultured in the presence of IL-2. Cells were then co-cultured and the ability of iDCs to induce surface mobilization of CD107a in autologous-activated NK cells was assessed. As seen in Fig. 2a, iDCs derived from HIV-negative patients induced degranulation of NK cells, whereas dendritic cells derived from HIV-infected patients did not induce increased degranulation. Activated NK cells from HIV-negative and resistant individuals were comparable in their ability to mobilize CD107a after stimulation with K562 as target cells (Fig. 1). Interestingly, dendritic cells from HESN induced significantly higher levels of degranulation of autologous NK cells than not only those from HIV-infected but also those from HIV-negative individuals. Killing of iDCs by activated human NK cells is known to be mediated predominantly through NKp30 and is lost as dendritic cells mature, an effect attributed to up-regulation of MHC class I molecules . However, as seen in Table 1, nonactivated NK cells from HIV-resistant donors do not appear to express higher levels of NKp30. Additionally, iDCs derived from these individuals do not express different levels of MHC class I molecules (data not shown).
Monocyte-derived dendritic cells from viraemic HIV-1 patients have been previously reported to produce less IL-12, and to be defective in inducing IFN-γ secretion from autologous NK cells . To test if this interaction is also different in HIV-resistant individuals, MoDCs were co-cultured with activated NK cells at different E:T ratios for 48 h, supernatants were collected and cells were stained for intracellular production of IFN-γ⋅ As seen in Fig. 2b, iDCs derived from HIV-negative individuals induced intracellular production of IFN-γ in NK cells, whereas dendritic cells derived from HIV-positive individuals failed to induce intracellular production of IFN-γ, in agreement with previous reports. Interestingly, dendritic cells from HESN individuals induced significantly higher intracellular production of IFN-γ in autologous NK cells when compared to both those HIV-infected, but also those from HIV-negative, susceptible donors.
The levels of IFN-γ and IL-12 (p70) released to the supernatants of the dendritic cell–NK co-cultures were measured by ELISA to further ascertain the efficiency of the NK–dendritic cell interaction in these three groups of individuals. Similar to the intracellular staining for IFN-γ in autologous NK, and in accordance with published data, activated NK cells did not produce detectable amounts of IFN-γ unless they were co-cultured with dendritic cells (Fig. 2c). Furthermore, the amount of IFN-γ secreted by autologous NK cells in response to stimulation with iDC was lower in supernatants from samples from HIV-infected individuals than in those from HIV-negative. Importantly, the amount of IFN-γ was significantly higher in supernatants from samples collected from HESN individuals than in those from either HIV (+) or HIV(-) study participants.
Similarly, the amount of IL-12 secreted by dendritic cells in response to autologous NK cells was lower in supernatants from HIV-infected individuals than in those from healthy controls (Fig. 2d). Interestingly, the amount of IL-12 secreted by dendritic cells from HESN participants appeared to be higher than in supernatants from samples from uninfected individuals.
As previously shown , our results support the observations of impaired iDC–NK interaction in HIV-infected individuals. We report here for the first time to our knowledge that the ability of activated NK cells to eliminate autologous iDC is greater among HESN. Additionally, iDCs from resistant individuals induce more IFN-γ production by NK cells, indicating that the overall strength of the interaction of NK cells with iDC is greater among those HESN individuals.
Interestingly, both interactions are known to be mediated by NKp30. However, the level of expression of NKp30 was examined in freshly isolated NK cells, and no differences between the three groups studied were observed. Rather than a role for NKp30 expression differences in resistance, perhaps differences in expression could be seen within the HIV-positive study participants, since clear differences in NKp30 expression are detected in individuals with high viral load. Furthermore, IL-2-activated NK cells of HIV-resistant patients do not appear to induce more efficient killing of target cells since their ability to mobilize CD107a in response to stimulation with K562 cells was comparable to those from HIV-negative patients (Fig. 2a). Although, it has been shown that K562 cells trigger NK cell activity mainly through NKp30  and NKp46  another major difference to the killing of iDC is that, in contrast to K562 which do not express MHC class I molecules and therefore do not induce inhibitory signals, iDCs express relatively high amounts of MHC class I molecules . Additionally, the experiments were performed in an autologous setting ensuring that the degranulation of NK cells observed is not due to MHC class I mismatch. The observed differences in killing between HIV-susceptible and resistant individuals do not appear to be due to higher expression of MHC class I molecules by dendritic cells in the resistant samples since these cells expressed comparable levels of HLA-DR.
Mounting evidence points to the importance of dendritic cell–NK interaction in shaping the subsequent host response to HIV – that is, the ability of NK cells to eliminate iDC may be important in decreasing the number of targets presented to HIV, thus contributing to the resistant phenotype. Taken together, our data suggest that despite the absence of phenotypic differences in the expression of activating receptors and activation markers on freshly isolated NK cells, the activated NK cells from HIV-resistant individuals are capable of a more robust degranulation and IFN-γ production with a trend towards more efficient killing of iDCs. Dendritic cells from HESN produced significantly higher levels of IL-12 and induced stronger degranulation of autologous NK cells, emphasizing the importance of the NK–dendritic cell axis in the regulation of immune responses. Whether this increased IL-12 production leads to substantial differences in the ensuing adaptive responses was not assessed in the present study. The absence of differences in MHC or NKp30 expression suggests that additional mechanisms may be contributing to these observed interactions. The significance of these findings remains to be elucidated.
H.G. – study design, data collection and analysis, writing of manuscript. Y.K. – study design, manuscript editing; J.K. and T.B.B. – study design and manuscript editing; M.K. – sample collection and study design; F.A.P. – study design; O.M. and A.F.A.M. – study design, data analysis, manuscript preparation. All authors have read and approved text submitted.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The work was supported by the Science and Technology International Collaboration (STIC) Fund of the Department of Science, Technology, Energy & Mines of the Province of Manitoba. Funding was also provided by the Global Research Exchange Program of the Canadian Friends of the Hebrew University, the Bill and Melinda Gates Foundation, and the Canadian Institutes of Health Research (CIHR) through the Grand Challenges in Global Health Initiative to F.P. F.P. is the Canada Research Chair in Resistance and Susceptibility to Infection group.
Conflicts of interest
There are no conflicts of interest.
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