The Real Function of NK Cells in vivo

When killers become helpersJacob Hanna1,2 and Ofer Mandelboim1

1 The Lautenberg Center for General and Tumor Immunology, The Hebrew University, Hadassah Medical School, Jerusalem 91120,

Israel2 The Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA

Opinion TRENDS in Immunology Vol.28 No.5

Since their initial characterization by Kiessling over35 years ago, natural killer (NK) cells continue toconstitute an area of intensive discovery in the immu-nology field. Although most of the research effortsconcentrated on characterizing the role of NK cells intumor prevention and fighting infection through thekilling of dangerous cells, several recent findings high-light unexpected non-cytolytic functions of human andmouse NK cells. Such functions include promotingplacental tissue development, antigen presentationand stimulation of T cells, priming of macrophagesand dendritic cells, reducing transplant tissue rejectionand several others.

IntroductionNatural killer (NK) cells comprise �10% of peripheralblood lymphocytes and originate in the bone marrow fromCD34+ hematopoietic progenitor cells, and eventuallypopulate different peripheral lymphoid and non-lymphoidorgans [1]. It is well established that these innate effectorcells are key players in limiting viremia and tumor burdenbefore the onset of adaptive T and B cell immunity [2]. Thecrucial in vivo importance of these cells has been empha-sized by studying NK-deficient patients and mouse modelsin which dysfunction or depletion of NK cells results infrequent, severe viral infections and increased sensitivity,especially to viruses of the herpes family [3,4]. However,recent studies suggest a more complex view of NK cellfunctions and implicate them as major regulators of differ-ent immune and non-immune processes in vivo, in additionto their ‘classical’ role in eliminating hazardous cellsthroughout the body by direct killing. Here, we focus onstudies elucidating novel NK roles in regulating decidua-lization and placental development in pregnancy, and inthe T cell-mediated adaptive immune response in humansand in mice [5–18]. We argue that these findings challengethe current status quo in estimating the in vivo functions ofNK cells, and assign significant complexity to NK cellinteractions in the context of systemic responses.

Understanding the role of NK cells in reproductiveimmunologyThe maternal–fetal interface is a dynamic site in whichfetal-derived trophoblast cells interact with maternal uter-ine tissue that includes immune cells, which constitute40% of the cells in the human decidua [19]. Detailed

Corresponding author: Mandelboim, O. (oferman@md2.huji.ac.il).Available online 2 April 2007.

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phenotypical analysis of this population has revealed aunique complement of immune cells, which is unlike thatseen in other tissues or mucosal surfaces. In humans, over85% of these cells were NK cells with a CD56brightCD16�,but not CD56dimCD16+, phenotype (Box 1 and Figure 1),whereas other immune cells are sparsely found in thistissue [20]. The high infiltration level of maternalCD56bright cells in the decidua puts them in close apposi-tion with stromal cells and invasive fetal trophoblasts [21].Understanding the biology of decidual NK (dNK) cells hasposed a major challenge for reproductive immunologists.Despite the extensive and valuable research performed onthe decidual CD56bright NK subset, the vast majority ofstudies performed focused on trying to characterize whyand how these cells do not exert cytolytic functions. How-ever, the question of what the in vivo functions are, andwhat this unique subset actually does in the humandecidua, remained relatively neglected until a few yearsago [22]. The impressively diverse NK inhibitory mechan-isms that mediate repression of dNK cytotoxicity towardsfetal cells characterized so far have been generally viewedas part of a potential dNK ability to induce generalmaternal immune tolerance. In our opinion, one mustdifferentiate between these two immunological phenom-ena and develop a paradigm that the lack of cytotoxicity ofdNK cells is not a function but rather a quality of these cellsthat perhaps makes them suitable and wanted ‘residents’at the fetal–maternal interface, possibly to conduct otherimportant functions, and it does not necessarily prove thatthey are able to induce tolerance of other decidual immunecells towards the fetus. Decidual and systemic regulatory Tcells have been clearly shown to be able to suppresssystemic maternal immune responses and induce toler-ance towards conceptus foreign antigens in mouse modelsin vivo, and the depletion of those cells led to immediatefailure of gestation [23]. To the best of our knowledge, asimilar immune regulatory function for dNK cells has notyet been demonstrated.

NK cells support decidual tissue growthAlthough the in vivo function of dNK cells remained to bevaguely defined, the groundbreaking work of Croy’s grouplaid down the basis for a novel concept describingconstructive functions for mouse NK cells in vivo at thefetal–maternal interface and their involvement in tissuehomeostasis. The work of Croy’s group demonstrated thatdepletion of NK cells in mouse decidua resulted in unex-plained inadequate changes in the adaptation of blood

d. doi:10.1016/j.it.2007.03.005

Box 1. Human NK subsets

Human NK cells are characterized phenotypically by the presence of

CD56 and lack of CD3 and can be subdivided into two subpopulation

based on the density of the CD56 marker (bright or dim) and the

presence or absence of CD16 (+ or �) [39]. 90–95% of the NK cells in

the blood are CD56dimCD16+ cells, whereas the remainder are

CD56brightCD16� cells. Functional studies have generally shown that

CD56bright NK cells are more efficient in secreting cytokines,

especially IFNg, whereas CD56dim NK cells are professional killers

of hazardous cells in vivo [39,40]. The molecular mechanisms

underling the functional differences between these NK subsets have

been characterized in a series of studies (Figure 1). For example, the

CD56brightCD16� NK cell population was found preferentially to

express CD62 ligand and chemokine receptors CCR7 and CXCR4,

and a different repertoire of various adhesion molecules might

explain why this subset is enriched in various human secondary

lymphoid organs (e.g. lymph nodes and tonsils) and non-lymphoid

organs (e.g. human decidua and synovia of inflamed joints)

[17,25,41]. By contrast, CD56dim NK cells express higher levels of

CXCR1 and CX3CR1 chemokine receptors, which are linked to

lymphocyte migration to peripheral inflammatory sites. The mole-

cular mechanisms underlying the enhanced killing ability of CD56dim

NK cells are less defined. This cannot be attributed to different

expression levels of cytotoxic granules, granzyme and perforin

levels or surface expression intensity for NK lysis receptors. This

strengthens the speculation that differences in intracellular signal-

ing circuits between the two NK subsets are responsible for setting

the cytotoxic capability of NK cells. Indeed, the CD3z signaling

adaptor molecule, which mediates natural cytotoxicity receptor

signaling, is expressed at lower levels in CD56bright NK cells

compared with the CD56dim NK subset [15]. An additional unique

aspect of the CD56bright NK subset is its enhanced ability to produce

soluble innate protective factors against fungi and other pathogens

(e.g. amphiregulin and lysozyme) and to express immune-suppres-

sive cytokines (e.g. IL-10) under certain conditions in vivo [15,26]

Finally, Di Santo and coworkers have recently characterized a thymic

pathway for NK development in mice of a unique subset that has

low cytotoxic ability and is highly efficient at IFNg secretion [42].

This NK subset is identified by the unique expression of IL-7

receptor-a (IL-7Ra) and GATA3. Because the specific expression of

IL-7Ra on human CD56bright, but not on the CD56dim NK subset [15],

has been detected [42], it would be interesting to test whether

human CD56bright NK cells have a developmental stage in the

thymus.

202 Opinion TRENDS in Immunology Vol.28 No.5

vessels that normally occur in the maternal uterinemucosa following implantation. In a series of follow-upstudies, they went on to prove that dNK-derived interferon(IFN)g positively regulates the diameter of the lumen ofblood vessels during decidualization and thus facilitatesappropriate decidualization [18,24]. The concept of theexistence of such a constructive function for NK cells inthe decidua was reinforced by studies examining mechan-isms facilitating the recruitment of CD56bright NK cells tothe decidua. The unexpected finding that invasive fetaltrophoblasts were involved in attracting CD56bright NKcells through production of a distinct set of chemokines(mainly stromal cell-derived factor-1 and macrophageinflammatory protein-1a) [25] has altered the way thatfetal–maternal interactions are perceived. It suggests thatthe maternal CD56bright NK cells are actively recruited byfetal trophoblast cells to populate the decidua in physio-logical pregnancy, and that the ‘hostile’ relationshipthought to exist between fetal invasive trophoblasts andmaternal CD56bright NK cells should be reevaluated [25].Stronger support for the equivalent existence of such

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functions for dNK cells in humans came from the geneticstudy by Moffett and co-workers [13], who showed thatfetal humanmajor histocompatibility complex (MHC)HLAclass I, C (HLA-C) and maternal killer immunoglobulin-like receptor (KIR) interaction combinations known toinduce a strong dNK inhibition increased the likelihoodof pre-eclampsia, a disease of human placentation in whichproper trophoblast invasion and vascular remodeling areimpaired. The opposite was true regarding receptor–ligandcombinations favoring dNK cell stimulation. Theseobservations implied that dNK cells need to be appropri-ately activated to be able to exert functions, yet to beelucidated, that will reduce the likelihood of the develop-ment of pre-eclampsia. Indeed, strong evidence has beenprovided for the enhanced ability of human dNK cells toregulate trophoblast invasion and vascular remodelingthrough their professional ability to secrete an array ofangiogenesis-regulating molecules, chemokines and cyto-kines [6]. It was further demonstrated that these functionsare inhibited or stimulated by the expression of ligands forNK inhibitory and activating receptors, respectively, onfetal trophoblasts and the decidual stroma [6]. We hypoth-esize that, overall, NK receptor–ligand interactions favor-ing dNK activation are protective against pre-eclampsia bysupplying sufficient amounts of NK-derived growth factorsand chemokines to enable a certain threshold for the avail-ability of sufficient growth factor levels to be met, sub-sequently establishing adequate trophoblast invasion andvascular remodeling, and thereby reducing the risk of pre-eclampsia.

It is important to emphasize that these results donot ruleout thepossibility thatdNKcellsmight functionas immune-suppressive cells in the decidua. In fact, CD56bright NK cellshave been linked to the suppression of inflammatory uveitisand multiple sclerosis in humans through the production ofthe suppressive cytokine interleukin (IL)-10 [26,27]. Itwould be interesting to conduct experiments aimed at defin-ing whether decidual CD56bright NK cells can function as‘regulatory T cell-like cells’ and suppress the responses of Tcells and other immune cells through direct interactions orcytokine secretion.

What does it take to become a dNK cell?Onemight ask: why should decidual NK cells be consideredas NK cells? First, dNK cells have been shown to expressan array of NK-activating receptors, including NKG2D,NKp30, NKp44 and NKp46. Second, following stimulationwith the activating cytokines IL-2 or IL-15, purified dNKcells acquire the ability to kill a variety of target cells thatare considered to be classical target cells for peripheralblood-derived activated NK cells by utilizing these activat-ing receptors. In our opinion, these features are sufficientto consider decidual CD56bright NK cells as a unique NKsubset with distinct features and functions. If one acceptsthis claim, then a major question that arises is: whatmakes decidual CD56bright NK cells different from periph-eral blood NK cells, including peripheral blood CD56bright

NK cells? We hypothesize that several microenvironmen-tal stimuli in the decidual tissue, and the complex inter-actions between dNK cells and neighboring immuneand non-immune cells at the fetal–maternal interface,

Figure 1. A schematic diagram of human NK CD56bright and CD56dim subsets. These subpopulations have distinct differences in the expression of several molecules. The

differentially expressed genes encompass members of a variety of functional protein groups, including cell surface receptors, adhesion molecules, secreted proteins, cell

cycle regulators, etc. Schematic presentation of selected key differences is shown. Please refer to Box 1 for a brief summary describing human NK subsets.

Opinion TRENDS in Immunology Vol.28 No.5 203

facilitate the enhancement of certain functions ofCD56bright NK cells. These unique functions include cyto-kine and growth factor production. In addition, theseinteractions between dNK cells and the surrounding cellsfurther inhibit their ability to induce damage on localtissue by killing neighboring semi-allogeneic fetal cells.The unique function of dNK cells might be regulated byestrogen and progesterone during pregnancy because dNKcells express receptors for these hormones [6,28]. Tropho-blast-derived soluble factors, such as solubleHLA-G, whichinduced the secretion of IL-8 by NK cells [29], might alsoparticipate in ‘educating’ dNK cells, and the physiologicalstress hypoxia in decidual tissue might influence NK cellfunctions. Indeed, tissue stress, such as irradiation, hasbeen shown to induce the expression of ligands for NKreceptors that stimulate NK cells [30]. It would be inter-esting to evaluate whether hypoxic stress in the deciduainduces the expression of ligands for dNK-activating recep-tors, which, in turn, further promotes growth factor pro-duction by the these cells. In direct continuation with this,the long-term exposure of dNK receptors to physiologicallyexpressed activating ligands for NK receptors on decidualcells might alter the behavior of dNK cells. Similarly, inmouse in vivo models in which NK cells were chronicallyexposed to ligands for NKG2D receptors, an ‘exhausted’status was observed and the production of cytokines suchas IFNg was enhanced [31]. Conducting experiments bywhich peripheral blood CD56bright NK cells are chronicallyexposed to ligands for NK-activating receptors and otherpotential stimuli in the decidua, and then examining themfor acquisition of decidual-like NK cell properties, mightprovide crucial insights into dNK cell biology.

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Novel positive regulatory roles for NK cells in theadaptive immune responseMouse cytomegalovirus infection models demonstratedpreferential distribution of IFNg+ NK cells near marginalzone areas of secondary lymphoid organs in vivo, whereantigen-presenting cells [APCs; mostly dendritic cells(DCs)] accumulate and prime T cells [32]. These obser-vations prompted scientists working in the field to studythe influence of NK cells on APC–T cell crosstalk. Indeed,much attention has been given to the interesting inter-actions between NK cells and DCs. CD8a DCs were shownto induce selective expansion of NK cells in vivo throughsecretion of IL-12 and IL-18 [33]. Conversely, NK cellsinfluence the activation and maturation of DCs. Interest-ingly, the interactions between immature NK cells andDCs can lead either to DC maturation or to their death invivo. Both outcomes are largely dependent on the inter-action between the NKp30 receptor and an unknownligand that is expressed on the surface of immature DCs[34]. Another aspect of the NK ‘helper’ function arises fromrecent evidence indicating that NK cells can be induced tofunction as non-cytotoxic ‘helper’ cells following stimu-lation with IL-18 [35]. This cytokine induces IFNg

secretion from NK cells and thus enables DCs to secreteIL-12p70, leading to T helper 1 (Th1) polarization [35].Interestingly, unlike IL-2 stimulation, which leads toincreased NK cell cytotoxicity and killing of immatureDCs, exposure to IL-18 did not affect cytotoxicity anddid not promote DC killing by NK cells. This supportsthe notion that the functions of NK cells as ‘effector’ and‘helper’ cells represent two independent mechanismsthat might be controlled through separate pathways. An

204 Opinion TRENDS in Immunology Vol.28 No.5

indirect in vivo role for NK cells in priming the Th1 CD4+ Tcell response by providing IFNg in the lymph nodes hasalso been shown [12]. Injection of mature DCs with adju-vant led to CXCR3-dependent recruitment of NK cells tothe lymph nodes, where they provided an initial source ofthe IFNg necessary for Th1 polarization. Depletion of NKcells resulted in a reduced Th1 response and was depen-dent on IFNg production from NK cells.

In spite of these intriguing observations characterizingindirect cytokine-mediated mechanisms for the regulationof T cell adaptive immune responses by NK cells, it wasunclear whether NK cells might directly initiate or propa-gate such responses through direct contact-dependentintercellular interactions. Studies have demonstrated thathuman NK cells efficiently enhance CD4+ as well as CD8+

T cell proliferation in response to antigen-specific stimu-lation or anti-CD3 treatment. This process is dependent ondirect contact-mediated interactions between ligands for Tcell receptor (TCR) co-stimulatory receptors expressed onstimulated humanNK cells (e.g. CD80, CD86, CD70, OX40ligand and 2B4 receptors) and their counterparts

Figure 2. Regulation of the adaptive immune response by NK cells. (a) Indirect role fo

(b) Activated NK (ANK) cells, which upregulate a variety of ligands for TCR co-stimulato

response in peripheral inflammatory sites and in lymph nodes by co-stimulating T

dependent interactions have not been demonstrated so far. (c) Direct antigen presentatio

after the killing of target cells and are able to present antigens derived from their targets

IFNg is shown as brown vesicular structures, target cells in pink, naive and memory T ce

are shown as red cells with blue nuclei.

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expressed on T cells (e.g. CD28, CD27, OX40 and CD48)[8,9,14,15] (Figure 2). Moreover, activated human NK cellsexpress MHC class II and have the capability to presentantigens directly and stimulate CD4+ T cell proliferation invitro [14]. Therefore, activated humanNK cells possess notonly the required co-stimulatory molecules for potentialinteraction with activated CD4+ T cells, but also have thecapacity to process and present antigens through MHCclass II (Figure 2). It is difficult to provide formal proof ofthis interaction in vivo in humans owing to obvious limita-tions. Unfortunately, because activated mouse NK cells(unlike humanNK cells) do not express MHC class II, micedo not provide a relevant or appropriate model to examineMHC class II TCR-dependent CD4+ cell interactions withNK cells [9]. Although DCs are considered to be the mostpotent APCs, the fact that activated NK cells expressMHCclass II, CD86, CD80, CD70 and OX40L strongly suggeststhe possibility that they might also communicate directlywith CD4+ cells.

Where might NK cells and T cells interact? In humans,CD56bright NK cells are found in T cell-enriched areas in

r NK cells in T cell activation by professional APCs (e.g. DCs) by secreting IFNg.

ry receptors, might have a crucial role in vivo in potentiating the adaptive immune

cells through direct intercellular interactions. In vivo evidence for such contact-

n by activated NK cells to CD4+ T cells. NK cells can acquire the APC-like phenotype

to naive and memory T cells, and thus function as a unique subset of APCs in vitro.

lls in yellow, stimulated T cells are shown as red cells with red nuclei and ANK cells

Outstanding questions

Important studies that should be carried out to ascertain the in vivo

function of NK cells

� Functional and phenotypical characterization of NK cells isolated

from pathological human blood and tissue samples (e.g. tumor-

infiltrating NK cells, NK from chronically infected tissues and HIV

patients, synovial fluid from the joints of rheumatoid arthritis

patients and NK cells from the cerebrospinal fluid of multiple

sclerosis patients, etc).

� Depicting the role of NK cells in mouse models of autoimmune

disease. For example, by developing tools for in vivo imaging of

NK cells and thus characterizing their recruitment to pathological

tissues and delineating their contribution to the initiation,

exacerbation or inhibition of such conditions.

� In depth study of potential immunosuppressive roles for NK cells

in inducing general immunosuppression (e.g. IL-10 secretion,

killing of hazardous APCs in allograft transplant tissues, etc.).

What triggers such immunosuppressive functions? Do human

dNK cells suppress the maternal response against the semi-

allogeneic fetal cells?

� What is the identity of the cellular ligands for natural cytotoxicity

receptors (e.g. NKp30 ligand on immature DCs, and NKp30 and

NKp44 ligands on trophoblasts and decidual stromal cells)? What

regulates the expression of these ligands?

� Do human CD56bright NK cells have a developmental stage in the

thymus, as is the case with mouse IL-7Ra+ NK cells? What

implications might this have on the licensing or education of NK

cells towards self?

Opinion TRENDS in Immunology Vol.28 No.5 205

human lymph nodes and tonsils, and thus can be poten-tially in direct contact with naive T cells found in theirproximity [17]. CD56dim cells (Box 1) are enriched ininflammatory peripheral organs, such as the liver andlungs, early during the immune system counterattackagainst invading pathogens or transformed cells, and thusmight directly stimulate T cells recruited to the same sites[36]. Importantly, during a viral or bacterial infection, NKcells can be exposed to an environment containing IL-2,IL-12 or IL-15, and potential ligands for NK-activatingreceptors or immune complexes that engage CD16 [37],thereby providing the stimuli needed for induction of theAPC-like phenotype and enabling them to interact withactivated or naive T cells.

In vivo evidence for antigen presentation by NKcells after killing in miceIn vitro studies in human NK cells demonstrated theirability to utilize their cytotoxic features to kill target cells(e.g. influenza-infected fibroblasts), acquire antigens fromthem and present them to T cells in an antigen-specificmanner, a process called ‘presentation after killing’ [14](Figure 2). Because of the limitations mentioned earlier,it is nearly impossible to evaluate these interactions inhumans in vivo or in mice. Interestingly, two recent reports[5,7] have substantiated the hypothesis for the presence ofantigen presentation after killing in vivo [14], by character-izing a unique bitypic NK–DC subset in mice that has notbeen shown to exist in humans. These studies described anovel immune cell subset that presents antigens to T cellsafter the killing of target cells. These cells were termedNK–DCs or IFN-producing killer DCs (IKDCs). These cellsexpress conventional NKG7, Klrc1, Klrk1, Klra, Klrb1c,as well as granzyme and perforin effector molecules [5,7].They also express significant levels of the conventional DCmarkersCD11candB220,andproducesubstantial amountsof IFNg, IL-12 and type I IFNs following stimulation.Remarkably, IKDCs kill typical NK target cells usingNK-activating receptors, following which DC-like antigen-presenting activity is gained, associated with upregulationof surface MHC class II and co-stimulatory molecules,which formally distinguishes them from classical NK cellsinmice that cannot acquire theAPC-like phenotype [5,7]. Inaccordance with our predictions from the human in vitrostudies, this unique NK–DC subset proved in vivo to be apivotal sensor and effector mechanism of the innate anti-tumor immune response by killing tumor cells and present-ing tumor-derived antigens to T cells, thereby eventuallyeradicating tumors and metastasis in vivo [5,7].

One major difference between the findings in humans[14] and the results from animal studies [5,7] is that, inmice, only the minor subset of NK cells that expressedCD11c and other DC markers had the ability to presentantigens to T cells after killing, whereas all human NKclones have been observed to have APC-like capabilities[14]. This can be explained by the fact that all human NKcells are CD11c positive [38]. It is tempting to hypothesizethat the human immune system, which is more evolutio-narily developed and complex, developed in such a waythat all human NK cells are equipped with NK–DC fea-tures because this subset is more efficient and has inte-

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grated significant killing and antigen-presentationcapabilities in all NK cells. In spite of the above evidenceand speculations, a direct role for antigen presentationafter killing is limited to a single mouse model, and furtherstudies arewarranted to substantiate and quantify the roleof NK cells in T cell response propagation in vivo.

Concluding remarksThe evidence discussed here suggests that NK functionalbiology is much more complex than previously thought.Pro-inflammatory and anti-inflammatory functions can bemediated through both cytotoxicity-dependent and -inde-pendent mechanisms by distinct subsets of NK cells. Thesecells are highly interactive and have the ability to regulatediverse immune (e.g. fighting infection, suppressing orpromoting autoimmunity, etc.) and non-immune (tissuehomeostasis) processes in the body. Key questions remainto be answered regarding human and mouse NK develop-ment, in vivo trafficking and intercellular interactions,among others. Future in-depth studies aiming to charac-terize NK behavior in the context of systemic responseswill lead to additional insights and better understanding ofthe roles of NK cells in vivo.

AcknowledgementsO.M. is supported by research grants from the Israel Cancer ResearchFoundation, The Israel Science Foundation, European Commission(QLK2-CT-2002–011112) and the Israeli Cancer Research Institute.J.H. is currently a Novartis Postdoctoral Scholar funded by the HelenHay Whitney Foundation. We thank Sa’ar Mizrahi for helping with thepreparation of the figures.

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