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. Author manuscript; available in PMC: 2014 Feb 15.
Published in final edited form as: J Immunol. 2013 Jan 23;190(4):1402–1406. doi: 10.4049/jimmunol.1203034

Antibody-dependent memory-like NK cells distinguished by FcRγ-deficiency1

Tianxiang Zhang 1, Jeannine M Scott 1, Ilwoong Hwang 1, Sungjin Kim 1
PMCID: PMC3623944  NIHMSID: NIHMS432551  PMID: 23345329

Abstract

Because NK cells lack gene recombination machinery and are thought to be relatively short-lived, whether NK cells can mount effective recall responses to re-infections by diverse pathogens for long-term is unclear. Here, we report that FcRγ-deficient NK cells, which we recently identified and termed g−NK cells, possess distinct memory features directed by Fc receptor-mediated antibody-dependent target recognition. The presence of g−NK cells was associated with prior cytomegalovirus (HCMV) infection, yet g−NK cell responses were not restricted to HCMV-infected target cells. In the presence of virus-specific antibodies, g−NK cells had greatly enhanced functional capabilities, superior to conventional NK cells, and were highly responsive to cells infected with either HCMV or HSV-1. Remarkably, the g−NK cell subset persisted for long-term at nearly constant levels in healthy individuals. Therefore, FcRγ-deficiency distinguishes an antibody-dependent memory-like NK cell subset with enhanced potential for broad anti-viral responses.

Introduction

NK cells are innate immune cells that contribute to host defense against viral infection and malignancy through rapid production of cytokines and the release of cytotoxic granules (1). In particular, NK cells play a crucial role in the control of herpesvirus infection, such as infection by HCMV (2–4). Despite being categorized as innate immune cells with relatively short lifespan (estimated at 10–20 d) (5, 6), recent studies of mouse models demonstrate adaptive immune features of NK cells, such as recall responses to certain haptens and viral antigens lasting up to several months (7–9). However, considering the fact that NK cells lack mechanisms for gene-rearrangement to generate antigen-specific receptors, the molecular basis for specific target recognition is poorly understood, and whether NK cells can mount memory responses to diverse pathogens is unclear (1, 10).

Recently, we found that about one-third of healthy individuals have circulating g−NK cells that express CD3ζ normally but are deficient for FcRγ (11), the two signaling adaptors associated with the Fc receptor CD16 (12). In the present study, we provide evidence that g−NK cells represent a distinct type of memory cell that primarily utilizes pathogen-specific antibodies instead of antigen-specific receptors for target recognition.

Materials and Methods

Human subjects and blood samples

PBMCs from healthy donors were obtained with informed consent or from discarded, de-identified leukoreduction filters (American Red Cross), as approved by the Michigan State University Biomedical and Health Institutional Review Board.

Phenotypic and functional analysis of NK cells

PBMCs were stained using antibodies for flow cytometry and CD56dimCD3−CD14−CD19− cells were gated as previously described (11). Briefly, cells were stained with antibodies for cell surface markers, then fixed in 2% formaldehyde. To distinguish g−NK cells, samples were treated with permeabilization buffer containing 0.1% saponin, followed by staining of intracellular proteins, including FcRγ (anti-FcεRI, γ subunit, Millipore) and CD3ζ (clone 6B10.2, eBioscience). MRC-5 lung fibroblast or human foreskin fibroblasts (HFF) were cultured in 96-well plates, infected (MOI=1) with HCMV (Towne, or AD169) or HSV-1 for 2 h, then washed with PBS to remove unadsorbed virus. PBMCs were cultured for 1–5 d with HCMV-infected cells, or 40 h with HSV-1- infected cells, in the presence of recombinant human IL-2 (10 U/ml). 6 h prior to analysis, 1 μl plasma, or purified IgG (Nab Protein A Plus Purification Kit, Thermo Scientific) was added along with brefeldin A (for cytokine analysis) or anti-CD107a with monensin (for degranulation). To exclude dead cells, LIVE/DEAD Cell Stain Kit (Invitrogen) was used.

ELISA

Serological status of donor plasma was determined using ELISA kits (MP Biomedicals) according to the manufacturer’s instructions.

Statistics

The Wilcoxon matched-pairs signed rank test was used for all assays except ELISAs, for which the chi-squared test was used. Differences were considered significant when p < 0.05 (GraphPad Prism).

Results and Discussion

Association between g−NK cells and HCMV infection

To explore the origin of g−NK cells, we compared the phenotypic characteristics of conventional NK cells, which express FcRγ, and g−NK cells from healthy donors. Analysis of killer cell immunoglobulin-like receptors (KIRs), which are expressed by subsets of NK cells (13), showed that g−NK cells had predominant expression of particular KIRs in many donors (Supplemental Fig. 1), suggesting that the g−NK cell subset is an outcome of expansion.

Considering the expansion and presence of g−NK cells in about one-third of healthy donors (11), we hypothesized that the presence of g−NK cells might be associated with prior infection by a common pathogen that does not cause illness in the presence of normal immune function. Previously, we found that compared to conventional NK cells, g−NK cells display markedly lower levels of NKp30 and NKp46 (11), the natural cytotoxicity receptors (NCR) associated with FcRγ (14). Interestingly, a subset of NK cells with a similar NCRlo phenotype has been found in HCMV- seropositive but not in HCMV-seronegative individuals (15). To examine the possible association of g−NK cells with HCMV, we tested for HCMV-specific antibodies in the plasma of 42 healthy donors, among which 17 donors had g−NK cells. HCMV-seropositivity correlated strongly with the presence of g−NK cells (p<0.0001); all donors with g−NK cells, except for one, were seropositive for HCMV IgG (Fig. 1A). By contrast, seropositivity for HSV-1 or HSV-2, two common herpesviruses, did not correlate with the presence of g−NK cells. Among the donors with g−NK cells, only 2 donors were weakly positive for HCMV IgM (data not shown), suggesting that most of these seropositive donors did not have a recent HCMV infection. Analysis of the one HCMV-seronegative donor with g−NK cells revealed a substantial number of memory T cells specific for the immunogenic HCMV tegument protein pp65 (data not shown) (16), indicating that this donor had also been exposed previously to HCMV. Thus, the presence of g−NK cells is strongly associated with previous exposure to HCMV.

FIGURE 1. Association of g−NK cells with prior HCMV infection.

FIGURE 1

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(A) Frequencies of g−NK cells among the CD56dimCD3−CD14−CD19− population within individual donors grouped according to IgG serological status for HCMV, HSV-1, or HSV-2 (n=42), (**p<0.0001, ns; not significant). (B) Comparison of marker expression on conventional NK (○) and g-NK (●) cells within CD56dimCD3−CD14−CD19− population. Dot graphs show mean fluorescence intensity (MFI) of indicated markers (*p<0.01, **p<0.0001).

Unlike conventional NK cells, g−NK cells showed predominant expression of NKG2C in many, but not all, donors (Fig. 1B). Notably, previous studies have shown that HCMV seropositive donors tend to have elevated numbers of NKG2C+ NK cells, which express high levels of CD57 and infrequent NKG2A (15–17). In line with this, g−NK cells also expressed high CD57 and low NKG2A levels regardless of NKG2C expression.

Requirement of antibodies for superior responsiveness of g−NK cells to HCMV-infected cells

Given the association with HCMV infection, we next sought to determine whether g−NK cells respond better than conventional NK cells to HCMV-infected cells. NK cell responsiveness was evaluated by examining intracellular IFN-γ after incubation of PBMCs with lung fibroblasts (MRC-5) either mock-infected or infected with the Towne strain of HCMV (18). While the overall production of IFN-γ by NK cells was slightly increased over background, g−NK cells produced less IFN-γthan conventional NK cells (Fig. 2A). Lower responsiveness of g−NK cells was also observed with a different strain of HCMV (AD169) as well as different host cells (Supplemental Fig. 2A). These data indicate that g−NK cells do not respond well to direct stimulation by HCMV-infected target cells.

FIGURE 2. g−NK cells display enhanced effector functions in response to HCMV-infected cells in the presence of HCMV-specific antibodies.

FIGURE 2

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PBMCs were cultured with mock- or HCMV-infected MRC-5 cells as indicated. (A and B) Flow cytometric analysis of IFN-γ production by conventional NK and g−NK cells from a representative donor following 3 d incubation. Inset values represent the relative percentage of IFN-γ+ NK cells. Line graphs show the percentages of conventional NK (○) or g−NK (●) cells that produced IFN-γ+ from several donors in the absence (A) or presence (B) of autologous plasma or purified IgG (Ab) as indicated. Dots connected by a line designate the same donor sample (**p<0.01). (C) Production of TNF-α by conventional NK or g−NK cells in the presence or absence of autologous plasma or purified IgG from several donors (**p<0.01). (D) Expression of CD107a in the presence or absence of autologous plasma or purified IgG following 2 d incubation (*p<0.05, **p<0.01).

Since we previously found that g−NK cells responded robustly to stimulation through mAb-mediated crosslinking of CD16 (11), we examined whether the presence of naturally-occurring antibodies against HCMV would impact g−NK cell responses. Using flow cytometry, we first confirmed the presence, albeit different concentrations, of antibodies that bound to HCMV-infected cells in the plasma of seropositive donors (data not shown). Addition of autologous plasma led to dramatic production of IFN-γby g−NK cells at levels significantly (p<0.01) higher than conventional NK cells (Fig. 2B). Although there was notable variation, presumably reflecting variations in antibody concentrations and subclasses between donors, the g−NK cells responded more robustly than conventional NK cells from all donors tested. The enhancing effects of plasma were dependent on the presence of infected cells, since plasma with mock-infected cells did not induce such responses. Addition of antibodies purified from autologous plasma also led to similarly high production of IFN-γby g−NK cells (Fig. 2B). These data indicate that plasma from all seropositive donors tested contained antibodies specific for viral antigen(s) expressed on the surface of infected cells that and triggered cytokine production through CD16. The higher responses of g−NK cells were also observed with the AD169 strain as well as with different host cells in the presence of plasma (Supplemental Fig. 2B, 2C). This robust responsiveness of g−NK cells was consistently observed over a wide range of concentrations of plasma and at different time points (data not shown). Furthermore, g−NK cells produced significantly (p<0.01) higher levels of TNF-α compared to conventional NK cells in the presence of plasma or purified antibody (Fig. 2C; Supplemental Fig. 2B, 2C).

To assess the cytolytic potential of NK cells, we examined the expression of CD107a, a degranulation marker, following incubation with HCMV-infected target cells. In the absence of antibody, the degranulation response of g−NK cells was significantly (p<0.01) lower than conventional NK cells (Fig. 2D). Compatible with our data, NKG2C+ NK cells in HCMV-seropositive donors were previously shown to respond poorly to HCMV-infected cells (19, 20). By contrast, in the presence of plasma or purified antibody, g−NK cells showed higher levels of CD107a (p<0.05), compared to conventional NK cells (Fig. 2D). Therefore, direct recognition is unlikely to be the primary mechanism for g−NK cell reactivity against HCMV-infected cells, and the enhanced cytokine and degranulation responses of g−NK cells to HCMV-infected targets are antibody-dependent. Taken together, the association with prior HCMV infection and enhanced antibody-dependent functional responsiveness of g−NK cells reveal distinct adaptive immune features that may lead to enhanced recall responses during reactivation or re-infection by HCMV.

Enhanced effector responses of g−NK cells to HSV-1-infected cells in the presence of virus-specific antibodies

Given the augmented responsiveness in the presence of HCMV-specific antibodies, we reasoned that g−NK cells could also respond robustly to other pathogens when pathogen-specific antibodies are available. To test this possibility, PBMCs from HSV-1 seropositive donors were co-cultured with HSV-1-infected cells in the presence or absence of autologous plasma. Similar to the HCMV-infection setting, IFN-γ production by g−NK cells was significantly higher (p<0.05) than from conventional NK cells in the presence of seropositive plasma (Fig. 3A, 3B). This plasma effect was antibody-specific, because the addition of autologous plasma lacking HSV-1-specific antibodies did not elicit such responses from HSV-1 naïve g−NK cells (Fig. 3B). These data indicate that the plasma from HSV-1-seropositive donors contained antibodies specific for HSV-1-derived antigen(s) on infected cells, and g−NK cells respond to HSV-1-infected target cells more robustly than conventional NK cells in an HSV-1-specific antibody-dependent manner.

FIGURE 3. Enhanced effector responses of g−NK cells to HSV-1-infected target cells in the presence of virus-specific antibodies.

FIGURE 3

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(A) Dot plots from one representative sample depict relative percentages of IFN-γ+ conventional NK and g−NK cells in the presence of autologous plasma after culture with HSV-1-infected MRC-5 cells. (B) Relative frequencies of IFN-γ+ conventional NK (○) and g−NK (●) cells from anti-HSV-1+ (n=6) or anti-HSV-1- donors (n=4) cultured with HSV-1-infected MRC-5 cells in the presence or absence of autologous plasma. Dots connected by a line designate the same donor sample (*p<0.05). (C) IFN-γ production by g−NK and conventional NK cells from a representative HSV-1 seronegative donor in the presence of purified allogenic IgG following co-culture with HSV-1- or HCMV-infected target cells. The anti-viral specificities of the plasma sources for purified IgG are indicated. All co-cultures were for 40 h.

To examine whether g−NK cells from HSV-1 naïve donors could respond to HSV-1-infected cells, antibodies were purified from non-autologous plasma and tested for the ability to enhance cytokine production. The addition of antibodies purified from HSV-1-seropositive donors led to greatly enhanced IFN-γproduction by g−NK cells over conventional NK cells from HSV-1-naïve donors co-cultured with HSV-1-infected cells (Fig. 3C). By contrast, antibodies lacking HSV-1 reactivity did not yield such responses. In parallel experiments, the addition of non-autologous HCMV-specific antibodies led to enhanced responses from g−NK cells cultured on HCMV-infected cells as expected. These data indicate that g−NK cells, regardless of prior exposure, can mount more potent functional responses to virus-infected cells than conventional NK cells if virus-specific antibodies are provided. Thus, g−NK cells have enhanced potential to mediate antibody-dependent cross-protection against a broad spectrum of viral infections.

Long-term persistence of g-NK cells

We next sought to determine if g−NK cells comprise a transient or stable population. Longitudinal studies showed that the relative frequencies of g−NK cells within the NK cell pool, as well as their absolute numbers, were nearly constant for 4–9 months after original assessments (Fig. 4A, 4B). The subset composition of g−NK cells was also stable, and there was no discernible change in functional responsiveness at these time points (data not shown). For donors that initially had no detectable g−NK cells (n=7), there was no appearance of g−NK cells over this period (data not shown). With respect to abundance, certain donors maintained large numbers of g−NK cells, in some cases exceeding the number of recirculating memory CD8+CD45RO+ T cells (Fig. 4B). These results indicate that the size of the g−NK cell pool is maintained long-termwith no indication of decline, an important feature of memory-type cells. Since the anti-apoptotic protein Bcl-2 is important for NK cell survival (5, 21), and is also elevated in memory CD8+ T cells (22), we analyzed expression of this protein. In all donors (n=11), g−NK cells expressed significantly higher levels (p< 0.01) of Bcl-2 than conventional NK cells (Fig. 4C). Analysis of the activation marker CD38, together with our previous data showing no detectable expression of activation markers CD69 and CD25, indicated that g−NK cells were not in an activated state (Fig. 4D). Finally, we analyzed several markers that have been associated with memory T cells (23). Although g−NK cells did not express CD45RO, CCR7, or CD127, the levels of CD44, CD11a and CCR5 were higher on g−NK cells compared to conventional NK cells (Fig. 4D, data not shown), reminiscent of the differences between naïve and memory T cells (23). Together, g−NK cells appear to be long-lived quiescent memory-type cells.

FIGURE 4. g−NK cells persist for long-term at nearly constant levels.

FIGURE 4

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(A) Percentages of g− NK cells among total NK cells collected at the initial time point and 4, 5 or 9 m later from healthy donors (n=9). (B) Absolute number of indicated subsets among 1×106 lymphocytes collected at initial time point (T1) and 4 or 5 m later (T2). Data are presented as mean ± standard error of the means (n=7). (C) Expression analysis of Bcl-2 in conventional NK and g−NK cells from one representative donor. Shaded peak is from control staining. Line graph shows the MFI of Bcl-2 expression (n=11) in conventional NK (○) and g−NK (●) cells. Dots connected by a line indicate the same donor sample (*p<0.01). (D) Marker expression on conventional NK and g−NK cells. Line graphs show MFI of indicated markers (*p<0.01, **p<0.001).

Collectively, our study reveals memory features of g−NK cells distinct from other memory cells. Unlike classical memory cells that use gene-rearranged antigen-specific receptors, g−NK cells utilize the germline-encoded Fc receptor that recognizes antibodies bound to target cells. Moreover, g−NK cells are unlikely related to antigen-specific memory NK cells described in mouse models (7–9), since FcRγ-deficiency abrogates CD16 expression on murine NK cells (24), and these memory-type NK cells disappear with a constant rate of decay (25). Importantly, the responses of g−NK cells are not restricted to a specific pathogen as antigen specificity is conferred through antigen-specific antibodies. Given the persistence and enhanced capabilities, g−NK cells are poised to impact the host immune response to diverse pathogens for long-term, particularly during later stages of primary infection, re-infection or chronic infection where pathogen-specific antibodies are available. Thus, g−NK cells may represent a new class of memory cells, which does not depend on antigen-specific receptors, for which FcRγ-deficiency itself provides a molecular signature. Finally, g−NK cells may have important implications for antibody-based therapies for infectious diseases and cancer, where the enhanced responsiveness of g−NK cells to antibody could significantly impact therapeutic efficacy.

Supplementary Material

1

Acknowledgments

We thank J. Drach and J. Breitenbach (University of Michigan) for virus stocks and host cells, P. Wallace for phlebotomy services, B. Siegfried and the American Red Cross for leukoreduction filters, A. Kim and T. Kakarla for technical support, K. Meek for critical reading of the manuscript, and W. Esselman for discussion and advice.

Abbreviations used in this article

g−NK

FcRγ-deficient NK cell

HCMV

human cytomegalovirus

KIR

killer cell immunoglobulin-like receptor

Footnotes

1

This work was supported by funding from the National Cancer Institute at the National Institutes of Health (5R21CA149476), Michigan State University, and National Agenda Project grant from the Korea Research Council of Fundamental Science & Technology, Republic of Korea, all to S.K.

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Supplementary Materials

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