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NK cells and interferons Rossella Paolini a, Giovanni Bernardini a, Rosa Molfetta a, Angela Santoni a,b,* a b

Department of Molecular Medicine, Istituto Pasteur Fondazione Cenci Bolognetti, ‘‘Sapienza’’ University of Rome, Italy IRCCS, Neuromed, Pozzilli, IS, Italy

A R T I C L E I N F O

A B S T R A C T

Article history: Available online xxx

The role of Natural Killer cells in host defense against infections as well as in tumour surveillance has been widely appreciated for a number of years. Upon recognition of ‘‘altered’’ cells, NK cells release the content of cytolytic granules, leading to the death of target cells. Moreover, NK cells are powerful producers of chemokines and cytokines, particularly Interferon-g (IFN-g), of which they are the earliest source upon a variety of infections. Despite being armed to fight against pathogens, NK cells become fully functional upon an initial phase of activation that requires the action of several cytokines, including type I IFNs. Type I IFNs are now recognized as key players in antiviral defense and immune regulation, and evidences from both mouse models of disease and in vitro studies support the existence of an alliance between type I IFNs and NK cells to ensure effective protection against viral infections. This review will focus on the role of type I IFNs in regulating NK cell functions to elicit antiviral response and on NK cell-produced IFN-g beneficial and pathological effects. ß 2014 Elsevier Ltd. All rights reserved.

Keywords: NK cells Type I interferon Interferon-g Cytotoxicity Antiviral response

1. Introduction Natural Killer (NK) cells are large granular lymphocytes that belong to the innate arm of the immune system and play an important role in the immune responses against certain microbial pathogens and tumour cells. They have been recently described as members of the group 1 of Innate Lymphoid Cells (ILCs), as they do not undergo RAG-dependent receptor rearrangement, and are strong producers of IFN-g [1]. NK cells develop from a common lymphoid precursor resident in the bone marrow (BM) that is considered the main site of their maturation. During viral infections, inflammation, tumour growth and invasion, NK cells are rapidly recruited from the blood and accumulate in the parenchyma of injured organs where activated NK cells can kill target cells and release inflammatory cytokines and chemokines, thus participating in the recruitment and

Abbreviations: cDC, conventional dendritic cells; HCMV, human cytomegalovirus; IFNAR, type I interferon receptor; IFN, interferon; LCMV, Lymphocytic Choriomeningitis Virus; MCMV, murine cytomegalovirus; NK cells, Natural Killer cells; pDC, plasmacytoid dendritic cells; KIR, Killer Ig-like receptors. * Corresponding author at: Department of Molecular Medicine, ‘‘Sapienza’’ University, Viale Regina Elena 291, Rome 00161, Italy. Phone: +39 06 44340632; fax: +39 06 44340632. E-mail address: [email protected] (A. Santoni).

activation of other leukocytes and in the modulation of accessory cell function [2,3]. Unlike B cells and T cells that express a single antigen specific receptor, NK cells are endowed with a multiple germ-line encoded cell surface receptor system recognizing ligands on virus-infected or tumour cells. All the receptors expressed by NK cells are not unique to this cell type, but are also present on cells of other lineages such as T cells or myeloid cells. Receptor expression on NK cells is highly regulated, with some receptors being oligoclonally distributed and/or expressed on subsets of NK cells. This complex receptor system is acquired during NK cell development, and consists of both inhibitory and activating receptors belonging to highly polygenic and polymorphic families [4,5]. Most inhibitory receptors specifically interact with MHC class I antigens. In humans, they belong to two distinct groups: the KIR family that comprises molecules binding to groups of human leucocyte antigen (HLA)-A, -B, -C alleles, and the C-type lectin receptors (i.e. CD94/NKG2A) specific for the widely expressed nonclassical HLA-class I molecule, HLA-E. In the mouse, the functional surrogates of the Killer Ig-like receptors (KIR) are the Ly49 receptors. NK cells also express activating counterparts of KIR and Ly49 receptors, which share the same ligand specificities of the inhibitory receptors, but are endowed with lower affinity. Among the receptors capable of triggering natural killing, the C-type lectin family NKG2D receptor recognizes the MHC class

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I-related A and B proteins (MICA and MICB) and the members of a family of proteins named UL16-binding proteins (ULBPs) in humans and of retinoic acid early inducible-1 gene (RAE-1) and UL-16 binding protein-like (MULT)-1 in mice [6]. These ligands are mainly expressed on the surface of tumour cells of different histotypes, infected, and stressed cells, and can be induced in response to DNA damage [7,8]. Other activating receptors, namely the Ig-like molecules NKp46, NKp44, and NKp30 belong to the Natural Cytotoxicity Receptor (NCR) family, but their cellular ligands are still elusive. Moreover, NK cells express a number of receptors acting as activating or co-stimulatory molecules such as CD2, CD244 (2B4), NKp80, beta1 and beta2 integrins and DNAM-1 (CD226). Based on the receptor complexity, activation of NK cell functions is, thus, the result of concomitant engagement of various activating and inhibitory receptors by the particular set of ligands on target cells. In most instances the inhibitory signals override the triggering ones [9], while during infection or transformation when MHC class I molecules can undergo down-regulation, activation of NK cells prevails. Despite already being armed for attack, NK cells require activation by type I interferons (IFN-a or IFN-b) or pro-inflammatory cytokines, such as interleukin-15 (IL-15), IL-12 and IL-18, in order to become fully functional and provide optimal host defense against infections [2,3]. This review overviews the role of type I IFNs in regulating NK cell anti-viral functions with an emphasis also given to the protective and detrimental effects of NK cell produced IFN-g.

2. Regulation of NK cell functions by type I IFNs NK cells have been classically considered capable of exerting their effector functions upon their first encounter with a potential target cell, such as a viral infected cell. However, they display effector functions following an initial phase of activation provided by dendritic cells (DCs) via a direct contact and/or through the release of several cytokines including IL-12, IL-15, IL-18 and type I IFNs, being this latter family of cytokines critical for early NK cell responses to several viral infections [2,3]. Type I IFNs are a family of innate cytokines consisting of several IFN-a subtypes in mice and humans, and one IFN-b subtype in both species [10]. As result of binding to their heterodimeric type I IFN receptor (IFNAR) broadly expressed on most cells, type I IFNs trigger a series of signalling cascades leading to phosphorylation of STAT (signal transducer and activator of transcription) molecules. STAT phosphorylation allows the formation of a transcriptional complex and the subsequent induction of several IFN-stimulated gene products endowed with antiviral activity [11]. Thus, exposure of cells to type I IFNs before infection induces an antiviral state that prevents productive viral infection. Type I IFNs are among the most potent regulators of NK cell activation [3]. The pivotal role of type I IFNs in the induction of NK cell cytotoxicity was firstly established in 1977 and 1978 from several independent groups. Trinchieri and Santoli [12] showed that type I IFNs activate human NK cell cytotoxicity in vitro against virus-infected cells. Welsh and Zinkernagel [13] demonstrated that NK cells are activated in vivo upon mouse infection with the Lymphocytic Choriomeningitis Virus (LCMV) and that this activation was promoted by virus-induced IFN production, whereas Gidlund and co-authors [14] showed enhanced NK cell cytotoxicity against sensitive target cells in mice treated with IFN inducers or with type I IFNs. In addition, Herberman’s group provided evidence that the level of NK-mediated cytotoxicity can be rapidly boosted in rats and mice upon inoculation with viruses or IFN inducers [15,16].

Subsequent reports from other groups demonstrated that type I IFNs potentiate NK cell cytotoxic activity increasing perforindependent cytotoxicity [17,18] and inducing TRAIL expression [19]. Moreover, type I IFNs, with the coordinated action of IL-12, activate NK cells to produce large amounts of IFN-g [17,20], contribute to NK cell homeostasis [21] and support NK cell proliferation driving the expression of IL-15 [18]. Although many cell types are capable of releasing type I IFNs in response to viral infection, the capacity to secrete high amounts of these cytokines appears to be restricted to specialized DCs. Several years ago, unusual cells capable of secreting high amount of type I IFNs were identified in human blood [22,23]. Subsequently, these cells were found to correspond to a population of cells with plasmacytoid morphology that are present in T cell-rich area of inflamed lymph nodes and are able to differentiate into mature DCs [24,25]. Notably, cells endowed with similar morphology and functions were also identified in mice and termed mouse IFN-aproducing cells (MIPCs) [26,27]. Thus, this subset of DCs, in both human and mice, represent the major producer of circulating type I IFNs in response to many viral infections. A pioneering work of Fernandez and co-authors formally demonstrated that also conventional DCs (cDCs) are able to activate NK cells through the contribution of both cell contactdependent and -independent mechanisms [28]. This observation was then confirmed in a variety of experimental settings [29,30], which clearly documented the existence of a complex bidirectional crosstalk between cDC and NK cells. cDC-mediated activation of NK cells results in increased NK cell cytotoxic activity and/or IFN-g production and can be induced by both resting and activated cDCs, the latter being more potent primers. Activated cDCs upregulate the expression of MHC, co-stimulatory and adhesion molecules and, can also express ligands for NK cell activating receptors depending on the stimuli received. In particular, the NKG2D ligands, namely MICA and MICB, are induced on human cDCs upon type I IFN stimulation and contribute to NK cell activation during DC/NK cell contact [31]. Moreover, cDCs produce most of the NK cell activating cytokines including type I IFNs [30]. Thus, type I IFNs play a multifaceted role in the survival, expansion and activation of NK cells particularly during primary infections. However, how type I IFN regulates NK cell activation is still a controversial field. 2.1. Type I IFN-mediated direct and indirect mechanisms of action Many studies have shown that type I IFNs can directly activate NK cells [32–34]; however counterevidence argues that a direct action of type I IFNs is not necessarily required to efficiently activate NK cells [35–37]. In 1978, Trinchieri and Santoli showed that addition of type I IFNs on in vitro cultured NK cells enhanced their cytotoxic potential [12], thus supporting a direct action of type I IFNs. More recently, adoptive transfer experiments have shown that a direct action of type I IFN on NK cells is necessary for the innate immune defence against vaccine virus infection [32] and adenoviral vectors [33]. Indeed, wild type (WT) NK cells transferred into IFNAR / knockout recipient mice were efficiently primed upon viral infection. Furthermore, in LCMV infection, Mack and coauthors demonstrated that direct type I IFN-induced signalling on NK cells is required for secretion of IFN-g in vivo [34]. In support to an indirect route of activation, a first study from Lucas and co-authors demonstrated that the action of type I IFNs on accessory DCs, but not on NK cells, was required for NK cell activation in response to TLR ligands [35]. In this context, type I IFNs would exert their stimulatory function by eliciting DC production of IL-15, which can then be trans-presented by DCs to NK cells [35].

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Furthermore, Zanoni and co-authors more recently reported that in inflammatory conditions elicited upon lipopolysaccharide exposure, type I IFNs could enhance NK cell activation by inducing IL-15 and its receptor not only in DCs but also in NK cells [38], thus suggesting that cis-presented NK cell-derived and trans-presented DC-derived IL-15 equally contribute to optimal NK cell activation. An additional finding supporting a dual role for type I IFN in mediating NK cell activation comes from adoptive transfer experiments of donor WT NK cells transferred in IFNAR / recipient mice before poly I:C stimulation [36]. The results of those experiments clearly demonstrated a requirement of type I IFN signalling on both NK and DC cells in order to promote NK cell activation. The direct and indirect type I IFN-mediated effects on NK cells are depicted in Fig. 1. Notably, in addition to their stimulatory role, type I IFNs have been reported to exert also negative effects. Indeed, although they promote NK cell proliferation in vivo [39,40], they fail to elicit NK cell proliferation in vitro but rather exert an anti-proliferative effect at high concentrations [41]. Moreover, type I IFNs can also negatively modulate IFN-g production [42]. This latter paradoxical effect may be important to protect against detrimental responses, since IFN-g can also contribute to cytokine-mediated disease [43]. In this regard, it is still unclear how NK cells are simultaneously predisposed to be good IFN-g producers, but tightly regulated to avoid inappropriate and potentially damaging responses. Recent evidence indicates that an important mechanism through which the overall response of NK cells to type I IFNs is promoted, relies on variations in the concentration of different STAT proteins and their accessibility to bind to IFNAR [44]. 2.2. Flexible signal of type I IFNs: a matter of STAT1/STAT4 balance IFNAR binding of type I IFNs preferentially elicits STAT1 and STAT2 phosphorylation, leading to the formation of transcriptionally active STAT1–STAT2 heterodimers or STAT1–STAT1 homodimers. In addition to STAT1 and STAT2, type I IFNs have been also reported to conditionally activate all of the STATs, including STAT4 [44]. A growing body of evidence indicate that the involvement of different STAT proteins, namely STAT1 and STAT4, in response to type I IFNs stimulates opposite gene programmes in NK cells. In

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particular, activation of STAT4 stimulates IFN-g production, whereas activation of STAT1 promotes cytotoxicity and IL-15 expression and inhibits IFN-g expression [18,38,42,44,45]. Interestingly, Miyagi and co-authors found that freshly isolated mouse NK cells possess high levels of STAT4, which is basally associated to IFNAR, and low levels of STAT1 proteins [45]. Thus, NK cell early exposure to type I IFNs results in a preferential phosphorylation of STAT4 over STAT1, leading to IFN-g production (Fig. 2). However, as firstly described in NK cells from LCMV-infected mice [42,45] and confirmed in NK cells from hepatitis C virus (HCV)-infected patients [20,46], a chronic exposure to IFN-a increases the expression level of STAT1 and promotes its preferential phosphorylation and activation, leading to an increase of NK cell cytotoxicity and a reduction of IFN-g production. This STAT1 over STAT4 phosphorylation can be also reproduced in vitro upon IFN-a stimulation of primary NK cells from healthy donors [47] and is further enhanced when patients with chronic HCV infection undergo IFN-a-based therapy [46]. Thus, the type I IFN-induced differentially pSTAT pathways based on variation in STAT ratio and accessibility to bind to IFNAR, could explain the NK cell phenotype observed in patients with chronic infection biased towards increased cytotoxicity and TRAIL expression and decreased IFN-g production [20,47]. 3. NK cell recognition of viral infected cells Even though the molecular mechanisms of NK cell activation during infection are not completely elucidated, increasing evidences demonstrate a role for NK cell activating receptors in early phases of virus replication as well as in the activation of adaptive response and long-term immunity [48,49]. In some cases NK cells can directly recognize viral components expressed on infected cells. A well-characterized example is provided by Mouse Cytomegalovirus (MCMV) infection in which NK cellmediated resistance is due to the expression of the activating NK receptor Ly49H [50,51]. In mouse strains positive for Ly49H this receptor recognizes the virus-encoded MHC class I-like glycoprotein m157 expressed on the surface of infected cells soon after infection; its ligation results in the release of cytolytic granules and secretion of chemokines and cytokines [52,53]. Compared to Ly49H NK cells, NK cell population expressing Ly49H preferentially proliferates and

Fig. 1. The direct and indirect activation of NK cells by type I IFNs. Upon viral infection type I IFNs is rapidly secreted by both cDC, together with other NK cell activating cytokines, and pDCs. Type I IFNs promote NK cell activation through both direct and indirect mechanisms of action: the direct action is achieved when type I IFNs bind to NK cell’s IFNAR, whereas the indirect effect requires a first activation of cDCs that can therefore act on NK cells. Both cis-presented NK cell derived and trans-presented DCderived IL-15 contribute to NK cell activation and proliferation. cDC, conventional dendritic cells; pDC, plasmacytoid dendritic cells; IFNAR, type I interferon receptor; IFN, interferon.

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Fig. 2. STAT activation upon type I IFN-mediated effects on NK cells. Resting NK cells express high level of STAT4, which is associated with IFNAR. Thus, NK cell early exposure to type I IFNs results in a preferential phosphorylation of STAT4 over STAT1, leading to IFN-g production. However, a chronic exposure to type I IFNs increases the expression level of STAT1 and promotes its preferential phosphorylation and activation, leading to an increase of NK cell cytotoxicity and a reduction of IFN-g production. IFNAR, type I interferon receptor; IFN, interferon.

undergoes a more persistent activation, displays increased effector function after the resolution of the infection, and subsequently mediates antigen-specific recall responses [54,55]. A direct recognition of MCMV-infected cells was also demonstrated in mouse strains negative for Ly49H receptor. In these strains, another NK activating Ly49 receptor, namely Ly49P, is able to recognize H2-Dk MHC class I molecules associated with peptides derived from MCMV-encoded protein m04 [56]. At present, there is no evidence for a human counterpart of Ly49H receptor that can directly recognize Human Cytomegalovirus (HCMV)-infected cells. However, a selective expansion of NK cells expressing the activating CD94/NKG2C receptor is demonstrated not only upon HCMV infection [57] but also in hepatitis B virus (HBV) and HCV infections [47,58], suggesting a role for this receptor in virus recognition in humans. In addition, activating NK receptors belonging to the KIR family could be involved in the recognition of viral components or virusderived peptides presented in association with MHC class I molecules in humans. Indeed, in Epstein–Barr Virus (EBV)-infected cells HLA-C molecules expressed in association with viral peptides bind activating KIR2DS1, triggering NK cell activation [59]. In addition, the expression of activating receptor KIR3DS1 in combination with HLA-Bw4 or KIR2DL3 in combination with HLAC1, respectively, significantly affects the susceptibility to some viruses, such as Human Immunodeficiency Virus (HIV) or HCV, and disease outcome, thus suggesting the involvement of these receptors in NK cell responses to viral infections [60]. Recognition of viral components by NK inhibitory receptors can also results in inhibition of NK cell effector functions. An MHC class I homologue HCMV-encoded molecule, pUL18, is expressed on the cell surface together with b2-microglobulin and is able to directly bind the inhibitory NK receptor LIR-1, thus allowing the virus to avoid NK cell immune-surveillance [61]. Moreover, the leader peptide of UL40 viral protein can bind the peptide groove of HLA-E promoting HLA-E membrane expression on the surface of infected cells and the engagement of the inhibitory NK receptor CD94/NKG2A [62]. Similarly to HCMV, also HCV-derived peptides bind HLA-E and stabilize its membrane expression [63]. A role in direct virus recognition has been also suggested for activating receptors belonging to NCR group that in humans are able to bind the hemagglutinin (HA)–neuroaminidase (HN) protein of influenza virus in vitro [64]. In particular, NKp46 deficient mice are more sensitive to influenza virus [65], supporting a role for NKp46 in the recognition of influenza virus.

In addition, some viral components, such as the pp65 tegument protein of HCMV [66], were shown to bind to the NKp30 receptor inducing the dissociation of the receptor from its transducing adaptor CD3z, thus affecting NCR-dependent NK cell function. In the absence of a specific receptor–ligand pair, NK cells play a crucial role in containing viral infections thanks to the ability of different viruses to down-modulate host MHC class I molecules and up-regulate stress ligands for activating NK cell receptors increasing susceptibility to NK cell killing [48,49]. In this context, both mouse and human CMVs encode proteins that down-modulate MHC class I molecules in order to avoid CD8+ T-cell responses [66], but this allows NK cell activation by ‘‘missing self’’ recognition. Moreover, ligands for the activating receptors NKG2D and DNAM1, that are poorly expressed on normal cells, are up-regulated on the surface of infected cells, promoting NK cell activation by ‘‘induced self’’ recognition and triggering co-activating signals leading to NK cell cytotoxicity and IFN-g production [6,67]. The induction of NKG2D ligands belonging to both MIC and ULBP families was firstly observed on HCMV-infected fibroblasts demonstrating a pivotal role for this receptor in NK cell-mediated killing of infected cells [68–70]. Subsequently, up-regulation of DNAM-1 ligands was demonstrated upon HCMV infection [71,72]. Similarly EBV, another herpesvirus known to cause persistent latent infections, up-regulates ULBP1 and the DNAM-1 ligand Nectin-2 on B cells during the switch from latent to reproductive lytic cycle, rendering these cells more susceptible to NK cellmediated killing [73]. HIV is also able to induce NK receptor activating ligands. In particular, HIV infection up-regulates the NKG2D ligands ULBP1-3 on virus-infected primary T cells [74,75], and the DNAM-1 ligand PVR on virus-infected CD4+ activated T cells [76]. Additional examples of up-regulation of NK activating ligands during infections are provided by the increased expression of MICB on human macrophages upon infection with Influenza A or Sendai virus [77], and up-regulation of MULT1 and Rae-1 in mice infected with poxvirus [78]. 4. NK cell function during viral infections The role of NK cells during viral infection has been investigated in the response to several pathogens, including herpesviruses such as CMV. The central role of NK cells in the response to MCMV was first established by antibody-depletion studies, which showed that C57BL/6 SCID mice (severe combined immunodeficient mice) that

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are normally resistant to MCMV, become highly vulnerable to infection when NK cells are removed [3,79]. Similarly, studies in patients affected by selective NK cell deficiencies have implicated NK cells in the control of the severity of infection with herpes viruses, HBV and HIV [80,81]. Moreover, the pivotal contribution of NK cells in viral clearance is also emphasized by several mechanisms evolved by different viruses to evade NK cell-mediated immune surveillance either modifying the ability of NK cells to recognize infected cells [48,66] or interfering with type I IFN production [82]. The antiviral activities of NK cells involve both the direct lysis of infected targets and the release of antiviral cytokines [3]. Antiviral cytokines, including IFN-g, act distantly to promote cell protection against viral infection, while the killing of infected target cells acts locally to prevent viral replication and spreading. Killing can be performed by NK cell release of cytolytic granules containing perforin and the serine protease family of granzymes, which activate the caspase pathway in target cells leading to their death by apoptosis. Although activated NK cells can up-regulate expression of TRAIL, thus promoting apoptosis of cells expressing receptors for this molecule, experiments in perforin deficient mice indicate that granule release is the main cytotoxic pathway used during viral infection [83]. 4.1. Regulation of NK cell responses to viruses by IFNs: protection vs immunopathology Type I IFNs and IL-12 are critical for resistance to virus as demonstrated in the immune response against MCMV infection. Type I IFNs are produced initially, by infected stromal cells in the spleen, and immediately after by pDCs, and directly control viral replication. Another subset of cDCs, promotes optimal priming of antiviral CD8+ T lymphocytes and NK cell activation. Both pDCs and cDCs produce IL-12 few days after MCMV infection. The cytokines IFNa/b, IL-12 and IL-15 have an important role in activating NK cellmediated killing of infected cells, IFN-g production and proliferation, respectively, whereas chemokines such as CCL3 (MIP-1a) produced by macrophages, promote NK cell trafficking to liver [3]. The key role of IFN-g in the promotion of NK-cell mediated antiviral defense was demonstrated in MCMV infection, where lack of NK cells but not of T and B cells led to impaired IFN-g production and correlated with increased viral load. The protective role of IFNg was shown in experiments with mice displaying mutations in key genes for IFN-g signalling, or by in vivo IFN-g neutralization experiments [84]. A role of IFN-g in human infections, including human herpesvirus 8 and CMV was also shown by evidences of increased susceptibility associated with mutations of IFN-g genes, although the role of NK cells in the production of IFN-g in this condition is unclear [85]. IFN-g promotes viral clearance by direct non-cytolytic mechanisms and control viral replication in vitro in a dose-dependent manner [86,87]. In addition, several evidences support a role of NK cell-derived IFN-g in the promotion of T cell response: NK cellderived IFN-g promotes the maturation and activation of DCs, macrophages and T cells [30,88] and can regulate Th polarization by inhibiting differentiation of IL-4- and IL-17-producing CD4+ T cells (Th2 and Th17 lineages) and inducing activated CD4+ T cells to differentiate into pro-inflammatory Th1 cells [89]. Furthermore, NK cell-derived IFN-g promotes liver infiltration by T cells by upregulating expression of the monokine induced by IFN-g, Mig/ CXCL9 [90]. Finally, IFN-g can also promote B cell class switching towards IgG capable of neutralizing viral particles [91]. Considering the importance of IFN-g production for protection, the kinetics and the level of its expression by NK cells in the early phase of viral infection may control the balance between viral

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clearance and persistent infection, thus affecting the severity of immune-mediated tissue damage. Indeed, a critical role of NK cells in influencing the extent of antiviral immune responses and in the control of associated immunopathology is also evident. This role is demonstrated by the exacerbation of tissue inflammation and damage induced by Theiler’s virus and coxsackie B3 viruses in mice depleted of NK cells [92]. Similarly, by controlling early MCMV infection, mouse NK cells facilitate the initiation of CD8+ T cell responses and dampen early, type I IFN-dependent immunopathology induced by strong pDC activation that occurs when virus load is elevated [93]. NK cell cytotoxicity may also represent a way of eliminating over-stimulated macrophages as genetic defects in cell-mediated cytotoxicity can associate with the occurrence of hemophagocytosis lymphohistiocytosis -like syndromes after viral infection [94]. Although NK cells directly contribute to antiviral defense and promote adaptive immunity at early phase of infection, at later times, when their ability to produce IFN-g decreases, they can negatively affect the capacity of adaptive immunity to limit persistent infection. Indeed, Ly49H+ NK cells that proliferate when adaptive immunity is ongoing during MCMV infection of perforindeficient mice, produce IL-10 to regulate the magnitude of adaptive immune responses and protect from CD8+ T cell-mediated pathology [95]. Similarly, increased proportions of NK cells with particular activating receptors producing IL-10 were observed during chronic HCV infections in humans [96]. A negative role of NK cells in the control of T cell-mediated immune response was also demonstrated in LCMV infection where NK cells do not play a direct antiviral activity, although in this context, tissue damage occurs because of uncontrolled viral replication [97]. Thus, LCMV infection can become chronic by the exacerbation of tissue inflammation and damage induced by Theiler’s and coxsackie viruses in mice depleted of NK cells [92] depending on the ability of adaptive immunity to rapidly clear the virus [98]. Similarly, in human HCV infection only a rapid and strong NK cell response early on during infection results in efficient T cellmediated antiviral response, while chronic infection is associated with persistent NK cell activation which is however linked to impaired IFN-g production and inability to clear virus [99]. The decreased or absent IFN-g production by NK cells may also unmask the active role played by NK cell cytotoxicity in suppressing T cell-mediated anti-viral responses in several infections, including LCMV. This was supported by the observation that antibody-mediated depletion of NK cells results in increased number and functionality of CD4+ and CD8+ T cell response that are more efficient in the elimination of LCMV infection [97,100]. Conversely, activated CD4+ T cells from mice with LCMV, MCMV, mouse hepatitis virus or vaccinia virus infection, were all more susceptible to lysis by activated NK cells, suggesting that NK cellmediated killing of activated CD4+ T cells is common in several viral infections and impairs the help provided to CD8+ T cellmediated protective response [97]. Interestingly, CD8+ T cells are protected against NK cell cytotoxicity in the acute phase of infection by type I IFN as demonstrated in the LCMV mouse model. Type I IFN acts directly on the virus-specific T cells by inhibiting NCR1 ligand expression or inducing up-regulation of several MHC-I molecules that function as ligands for inhibitory receptors [101,102]. These studies support previous observation showing that type I IFNs are important to drive CD8+ T cell differentiation. Indeed, T cells that do not perceive type I IFN signals fail to accumulate during certain infections while the level of MHC I expression by T cells in HCV patients correlates with virus control [103–107]. A number of evidence also demonstrate that NK cell-derived IFN-g-mediated T cell responses are not only protective, but can also have detrimental effects.

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Fig. 3. NK cell play opposite roles in the regulation of T cell-mediated anti-viral response during the course of infection. At early infection phase, the fast production of type I IFNs and other cytokines promote IFN-g production by NK cells. IFN-g favours the differentiation of viral-specific CD4+ and CD8+ T (CTL) cells. Virus spreading is thus inhibited by the direct action of NK cell-produced IFN-g and by CTL-mediated cytotoxicity. In a later infection phase, IFN-g production decreases while NK cell cytotoxic function and expression of IL-10 increase. NK cells can thus inhibit T cell-mediated antiviral response by direct killing or by blocking their differentiation in an IL-10 dependent manner. Thus, depending on NK cell ability to directly kill virus-infected cells, NK cells can promote viral clearance and tissue protection by T cells or be the cause of virus persistence provoking chronic T cell activation and tissue damage. CTL, cytotoxic T lymphocyte; IFN, interferon.

Studies in a mouse model of Respiratory Syncytial Virus (RSV) infection demonstrate that NK cell-derived IFN-g promotes lung immunopathology. At the early stage of infection, activated NK cells accumulated in the lungs and exert antiviral protection. At later times IFN-g production by NK cells was responsible for acute lung immune injury by mediating robust activation of T cells that were increased in infected lungs [108]. Overall, depending on the phase of infection (acute vs. persistent) and the type of pathogen, NK cells can differently influence the activation and function of several immune cells, thus affecting the equilibrium between protection from infection and promotion of pathology (Fig. 3). Acknowledgments The authors are supported by grants of the Italian Ministry of Health, the Italian Ministry of University and Research (MIURL.297 FAR), the Italian Association for Cancer Research (AIRC: an Investigator Grant and a Special Programme Molecular and Clinical Oncology-AIRC 5 per Mille), the Istituto Pasteur-Fondazione Cenci Bolognetti, and the Istituto Italiano di Tecnologia (IIT). References [1] Spits H, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, et al. Innate lymphoid cells – a proposal for uniform nomenclature. Nat Rev Immunol 2013;13:145–9. [2] Trinchieri G. Biology of natural killer cells. Adv Immunol 1989;47:187–376. [3] Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar-Mather TP. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol 1999;17:189–220. [4] Raulet DH, Vance RE, McMahon CW. Regulation of the natural killer cell receptor repertoire. Annu Rev Immunol 2001;19:291–330. [5] Lanier LL. NK cell recognition. Annu Rev Immunol 2005;23:225–74. [6] Raulet DH, Gasser S, Gowen BG, Deng W, Jung H. Regulation of ligands for the NKG2D activating receptor. Annu Rev Immunol 2013;31:413–41.

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[106] Cox MA, Kahan SM, Zajac AJ. Anti-viral CD8 T cells and the cytokines that they love. Virology 2013;435:157–69. [107] Oliviero B, Mele D, Degasperi E, Aghemo A, Cremonesi E, Rumi MG, et al. Natural killer cell dynamic profile is associated with treatment outcome in patients with chronic HCV infection. J Hepatol 2013;59:38–44. [108] Li F, Zhu H, Sun R, Wei H, Tian Z. Natural killer cells are involved in acute lung immune injury caused by respiratory syncytial virus infection. J Virol 2012;86:2251–8. Rossella Paolini obtained her PhD in Immunological Sciences in 1990 at ‘‘Sapienza’’ University of Rome. She was a Postdoctoral Fellow (from 1990 to 1993) and a Visiting Associate (from 1993 to 1995) in the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH), USA. Her current position is Professor of Immunology at ‘‘Sapienza’’ University of Rome. Her studies has been mainly focused on the identification of the molecular pathways regulating the fate of activating receptors in NK cells and mast cells, highlighting a critical contribution of the ubiquitin pathway in limiting the extent of NK and mast cell functional responses.

Giovanni Bernardini obtained his PhD in Immunological Sciences in 1999 at ‘‘Sapienza’’ University of Rome contributing to the cloning and functional characterization of new chemokine receptors. He then undertook a period of Postdoctoral training at Stanford University, California, USA (2000–2001), during which he mainly studied the signalling pathway regulating lymphocyte chemotactic response. He is Assistant Professor at ‘‘Sapienza’’ University of Rome. His current interests are focused on the analysis of the regulation of NK cell function by cytokines and chemokines, with particular attention dedicated to the ability of these factors to shape the inflammatory and anti-tumour immune response by regulating NK cell trafficking. Rosa Molfetta obtained her PhD in Immunological Sciences in 2003 at ‘‘Sapienza’’ University of Rome. Her current position is Researcher at ‘‘Sapienza’’ University of Rome. Her scientific activity has been focused on the molecular mechanisms regulating surface expression of activating receptors of NK cells and mast cells. Her current interests are focused on post-translational modifications regulating surface expression of NK cell activating receptor ligands on surface of infected and transformed cells.

Angela Santoni obtained her PhD in Biology at the University of Perugia in 1972. From 1975 to 1977 and from 1981 to 1983 she was a Postdoctoral fellow in Dr. Herberman’s laboratory at the Section of Natural Immunity (NCI) in the National Institutes of Health (NIH), USA, on the role of Interferons in regulating proliferation and cytotoxicity of Natural Killer cells. Returning in Italy she established an independent research group at ‘‘Sapienza’’ University of Rome where her current position is Full Professor of Immunology. From 2009 to present she is the Scientific Director of the Pasteur Institute in Rome (Cenci Bolognetti Foundation), and from 2010 Head of the Department of Molecular Medicine at ‘‘Sapienza’’ University. She is EMBO member, Past President of the International Society for Natural Immunity, and member of Academia Europæa the National Research Committee of the Welfare Ministry and of GAVI (Global alliance for Vaccination and Immunization) as Italian representative. Her research activity has been mainly aimed at understanding the mechanisms underlying the NK cell recognition, migration, and effector functions against tumour and viral infection. Ongoing studies are focused on the identification of the mechanisms regulating NK cell-mediated stress immunosurveillance and migration triggered by senescent cells.

Please cite this article in press as: Paolini R, et al. NK cells and interferons. Cytokine Growth Factor Rev (2014), http://dx.doi.org/ 10.1016/j.cytogfr.2014.11.003