Natural killer cell induction of tolerance

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Chapter Forty-Seven

Natural killer cell induction of tolerance Lina Lu, Alexandra Y. Zhang, William L. Camp, Shiguang Qian

Chapter contents

NK cell self-tolerance . . . . . . . . . . . . . . . . . . . . . . . .   618 Missing-self recognition hypothesis . . . . . . . . . . .   618 Inhibitory receptors that recognize MHC class I molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   618 Challenges to ‘missing self’ recognition hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   619 ‘Licensing’ concept . . . . . . . . . . . . . . . . . . . . . . . .   621 Non-MHC-class-I–specific NK-cell recognition . . .   621 Non-MHC-class-I–specific inhibitory receptors . . .   621 Achievement of self-tolerance without expressing inhibitory receptors specific for self-MHC class I molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   622 Continuous engagement of activation receptors induces NK cell tolerance . . . . . . . . . . . . . . . . . . .   622 NK cells in regulation of immune responses . . . . . .   622 NK and dendritic cell interaction . . . . . . . . . . . . . .   622 NK and T cell interaction . . . . . . . . . . . . . . . . . . . .   624 NK cells in transplantation . . . . . . . . . . . . . . . . . . .   624 NK cell tolerance and viral infection . . . . . . . . . . .   625 NK cells and maternal tolerance . . . . . . . . . . . . . .   626 Breaking NK cell tolerance for cancer therapy . . .   627

It is a mistake to try to look too far ahead. The chain of destiny can only be grasped one link at a time. Winston Churchill Abstract

Natural killer (NK) cells represent a potent first line of defence in immunity. They preferentially attack cells that

do not express or express low self-MHC class I proteins. However, accumulating data suggest that NK functional biology is more complex than previously thought. NK cells express many receptors, both stimulatory and inhibitory. The net balance of activating and inhibitory signals resulting from interactions with target cells determines the ultimate action to mediate killing or not. In addition to the receptors specific to self-MHC class I, various non-MHC stimulatory receptors on NK cells also participate in the decision making. NK cells can also function as immune regulators by producing proinflammatory cytokines and chemokines upon various stimuli, as well as delivering cytotoxic signals to influence other immune cells, thus achieving their role in regulating both innate and adaptive immune responses. Key words

Receptor, Self-tolerance, Major histocompatibility complex, Cytotoxicity, Apoptosis, Immune regulation, Dendritic cells, T cells, Viral infection, Transplantation

Natural killer (NK) cells are a major cell type of the innate immune system. Although NK cells do not express the specialized genes that are rearranged as T cell receptors, they are capable of discriminating self and foreign, as well as normal and diseased cells, thus, demonstrating the ability to attack transformed, infected and stressed cells but not normal self cells. How these cells are prevented from killing normal cells while attacking diseased cells is a major unresolved question for NKcell biology. The finding that the cells lacking self-MHC class I molecules are more sensitive to NK cells leads to the formulation of the ‘missing-self ’ recognition theory, which states that NK cells preferentially kill the cells that do not express or express low self-MHC class I. It 617

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was realized later that this recognition is governed by many receptors expressed on NK cells, including stimulatory and inhibitory receptors. The net balance of activating and inhibitory signals resulting from interactions with the target cells determines whether the NK cell becomes activated to produce inflammatory cytokines (such as IFN- and TNF-) to kill the target cells, or not (Lanier, 2005; Moretta et al., 2001; Yokoyama and Seaman, 1993). In addition to the receptors specific for self-MHC class I, studies have also shown that various non-MHC receptors on NK cells participate in the decision making. Although NK cells express several families of these inhibitory receptors, MHC-I molecules represent the essential ligands for inhibitory NK-cells receptors. NK cells often act as potent effector cells in the rejection of allogeneic bone marrow cells and solid organ transplants (Kean et al., 2006) and in the destruction of pathogen-infected cells. However, in certain circumstances, NK cells also express potent immunoregulatory properties that promote tolerance induction (Cooper et al., 2001). There is evidence that supports the theory that NK cells promote tolerance not by direct interaction with target cells, but by modulating responses of host immune cells via producing proinflammatory cytokines and chemokines upon various stimuli, and delivering cytotoxic signals to immune effector cells (Beilke et al., 2005; Yu et al., 2006). Thus, in addition to the surveillance of tumours and virus-infected cells, NK cells also contribute to regulating the nature and the extent of adaptive immune responses. Progress in the area of NK cells and tolerance to self- and nonself-antigens will be necessary for a comprehensive understanding of NK cell recognition and for facilitating tolerance induction to cell or organ transplants and autoimmune diseases.

NK cell self-tolerance NK cells can be activated by various endogenous self ligands, some of which are expressed by normal cells. How are NK cells prevented from attacking normal cells while ensuring reactivity to diseased cells? Engagement of the inhibitory receptors plays a central role in self-tolerance by NK cells, resulting in inhibition of cytokine production and cytolysis in order to maintain self-tolerance (Werner, 2008).

Missing-self recognition hypothesis MHC class I molecules represent the classical ligands for inhibitory NK-cell receptors. Almost all nucleated cells express MHC class I molecules that make them a supreme marker of self. For years, it has been thought 618

that self-cells are protected from NK cells because of their expression of MHC-class-I molecules that are recognized by the inhibitory receptors at the surface of NK cells, thus keeping NK cells non-responsive. In contrast, infected, or transformed cells that do not express sufficient levels of host MHC-class-I molecules for effective engagement of inhibitory receptors, are recognized by NK cells as non-self, and are killed (Karre et al., 1986; Ljunggren and Karre, 1990). This is the basis of the ‘missing-self recognition’, the capacity of NK cells to attack cells that lose or downregulate expression of some or all self-MHC class I molecules. This is not just limited to virally infected or transformed cells, since normal cells can be killed by NK cells if they are unable to express sufficient self-MHC class I molecules. A classic example of this hypothesis is that donor bone-marrow cells missing an MHC class I allele of the host are commonly rejected by NK cells (Ohlen et al., 1989).

Inhibitory receptors that recognize MHC class I molecules Many receptors are expressed on the surface of NK cells; some are stimulatory and some are inhibitory. It is widely accepted that expression of inhibitory receptors specific for self-MHC class I molecules on NK cells is essential in missing-self recognition (Figure 47.1). A set of inhibitory receptors is acquired during the development of NK cells. NK cells have been studied extensively in mice, rats and humans. At least three families of MHC class I–specific inhibitory receptors have been identified: the killer cell immunoglobulin-like receptor (KIR), the lectin-like Ly49 family and other receptors, including the CD94/NKG2A receptor and paired Ig-like receptor (PIR) (Table 47.1) (Lanier, 2005; Moretta et al., 1996; Vance et al., 1998; Yokoyama, 1995). There are strong analogies in these species, both in the receptors and functional pathways. For instance, the functions of Ly49 receptor family expressed on mouse NK cells are similar to KIR family receptors in human NK cells. However, the differences are obvious. KIRs are expressed in humans and other species except mice, while Ly49 receptors are expressed in mice, rats and other species, except humans. The CD94/NKG2A receptors are expressed across all species. Multiple inhibitory receptors can be expressed concurrently by each NK cell. Although not all of the inhibitory receptors may recognize self-MHC, during their development, eventually all mature NK cells express at least one inhibitory receptor specific for a self-MHC class I molecule in order to prevent self attack, which is proposed as the ‘at least one receptor’ model (Raulet et al., 2001). Two possible adaptations may be involved to modify the inhibitory MHC-I receptor repertoire, through either

Natural killer cell induction of tolerance

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Figure 47.1 l Basic model for NK cell tolerance and activation. The inhibitory receptor signal through MHC class I ligation counters the stimulatory receptor signal via its ligand on target cells, resulting in tolerance of NK cells. Upregulation of stimulatory ligand or downregulation of MHC class I on infected/transformed cells leads to NK cell activation.

a cellular selection process (i.e. selective expansion of the immature NK cells that express self-MHC–specific inhibitory receptors); or a probable “audition” of the receptors encoded by the genome until an inhibitory receptor that is specific for MHC-I molecules is expressed during the development of NK cells (Dorfman and Raulet, 1998; Held et al., 1996; Raulet et al., 2001; Roth et al., 2000; Valiante et al., 1997). NK cells that initially express only receptors that do not bind the self-MHC class I molecules cannot be suppressed by self-MHC class I molecules and are thus potentially auto-aggressive. Such cells may arise but fail to mature and may not contribute to the mature NK cell pool. By these mechanisms, an initially arbitrary NK repertoire might be selectively modified into a mature NK cell pool that expresses at least one, if not multiple, inhibitory receptors, specific for self-MHC class I molecules. In the “sequential-cumulative model”, it was proposed that during NK cell development, certain Ly49 genes are induced such that developing NK cells continue to collect new receptors until recently expressed inhibitory receptors engage self-MHC class I molecules with adequate strength (Dorfman and Raulet, 1998; Hanke et al., 2001; Roth et al., 2000). After interaction with their target-cell ligands, the inhibitory receptors become tyrosine phosphorylated on their immunoreceptor tyrosine-based inhibitory motifs (ITIMs). NK cell activation and its effector responses are then inhibited by recruiting intracellular phosphatases, SRC homology 2 (SH2)-domain-containing protein tyrosine phosphatase 1 (SHP-1) and 2 (SHP-2), resulting in an inhibitory signal. Otherwise, if the target

cell ligands can be identified by the activation receptors, NK cell effector responses (i.e. cytokine production and target cell lysis) will be executed.

Challenges to ‘missing self’ recognition hypothesis Although many studies over two decades of research have supported the ‘missing self ’ hypothesis that the interaction between MHC class I molecules and the inhibitory receptors on NK cells is relevant to the generation of NK cell self tolerance, this hypothesis has been challenged by several fundamental observations. A logical extension of this theory is that MHC class I deficiency should experience robust NK cell autoreactivity. Indeed, the data from both humans and mice show that a lack of MHC class I expression does not demonstrate excessive NK cell activity. MHC class I-deficient mice, such as 2 m/, TAP1/, or H2-D/K/ mice, contain a relatively normal number of NK cells and do not succumb to autoimmunity. On the contrary, the NK cells derived from MHC class I deficient hosts, although otherwise normal, demonstrate an inhibitory ability to lyse cells devoid of MHC I molecules. These MHCclass-I–deficient NK cells, unlike the NK cells derived from wild type hosts, do not reject MHC-I-deficient grafts (Bix et al., 1991; Vitale et al., 2002), suggesting that NK killing activity is not only dependant on the expression of inhibitory receptors , but also may be affected by MHC class I expressed on their surface. 619

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Table 47.1  Main inhibitory receptors regulating NK cell functions

Name

Alternative names

Species

Type of molecule

Ligand(s)

KIR family

CD158

KIR-2DL1

CD158a

Human

Ig-like

HLA-C

KIR-2DL2

CD158b1

Human

Ig-like

HLA-C

KIR-2DL3

CD158b2

Human

Ig-like

HLA-C

KIR-2DL4

CD158d

Human

Ig-like

HLA-G

KIR-2DL5a

CD158f1

Human

Ig-like

ND

KIR-2DL5b

CD158f2

Human

Ig-like

ND

KIR-3DL1

CD158e1

Human

Ig-like

HLA-Bw4

KIR-3DL2

CD158k

Human

Ig-like

HLA-A3, -A11

KIR-3DL3

CD158z

Human

Ig-like

ND

KLR-A family

Ly49 (functions are similar to KIR family in humans)

KLR-A1

Ly49a

Mouse

C-lectin-like

H-2D

KLR-A3

Ly49c

Mouse

C-lectin-like

H-2K, D

KLR-A5

Ly49e

Mouse

C-lectin-like

ND

KLR-A6

Ly49f

Mouse

C-lectin-like

H-2D

KLR-A7

Ly49g

Mouse

C-lectin-like

H-2D

KLR-A9

Ly49i

Mouse

C-lectin-like

H-2D, MCMV

KLR-A17

Ly49q

Mouse

C-lectin-like

H-2K

LILRB family

CD85

LILR-B1

CD85j

Human

Ig-like

HLA class I, HCMV

LILR-B2

CD85d

Human

Ig-like

HLA class I

LILR-B4

CD85k

Human

Ig-like

HLA class I

2B4

CD244

Human, mouse

Ig-like

CD48

CEACAM1

CD66a

Human, mouse

Ig-like

MHV

KLR-B1

CD161, NKR-P1a

Human

C-lectin-like

OCIL, CLEC2D

KLR-D1-KLR-C1

CD94-NKG2A (CD159a)

Human Mouse

C-lectin-like

HLA-E Qa-1b

KLR-B1b

CD161B, NKR-P1b

Mouse

C-lectin-like

OCIL

KLR-G1

MAFA

Human, mouse

C-lectin-like

Cadherin

LAIR-1

CD305

Human, mouse

Ig-like

Collagen

PIR-A

Mouse

Ig-like

CD99

PIR-B

Mouse

Ig-like

H-2D, K

Others

CEACAM1, carcinoembryonic-antigen-related cell adhesion molecule 1; HCMV, human cytomegalovirus; KIR, killer cell immunoglobulin-like receptor; KLR, killer cell lectin-like receptor; LAIR, leukocyte-associated immunoglobulin-like receptor; LILR, leukocyte immunoglobulin-like receptor; MAFA, v-maf musculoaponeurotic fibrosarcoma oncogene homolog A; MCMV, mouse cytomegalovirus; MHV, mouse hepatitis virus; ND, non-defined; PIR, paired immunoglobulin-like receptor.

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‘Licensing’ concept These observations raised an important question— whether or not the NK cells from MHC-I–deficient hosts are functionally defective (Dorfman et al., 1997; Salcedo et al., 1997). The answer is ‘yes’, based on many studies. NK1.1 is an activation receptor expressed by all NK cells in mice (Arase et al., 1996; Kim et al., 2002). Wild-type NK cells produced IFN- upon NK1.1 crosslinking. However, NK1.1-activated NK cells derived from either 2m-deficient or KbDb-deficient mice produce almost no IFN-. Further analysis revealed that other activation receptors also failed to stimulate IFN- production by these cells (Kim et al., 2005). Therefore, the activation receptors on NK cells from MHC-class Ideficient mice are functionally defective, indicating that MHC class I influences NK cell functional competence. MHC congenic mice have been used to address how MHC class I influences NK cell function. The data suggest that either naïve or pre-activated NK cells deficient in expression of known self-receptors (Ly49C, Ly49I, CD94/NKG2A, CD94-NKG2C or CD94-NKG2E) demonstrate self-tolerance but respond poorly to MHC class I deficient normal cells or tumour cells, suggesting that self-tolerance of NK cells can be established independently of MHC-mediated inhibition (Fernandez et al., 2005). More definitive studies were conducted using naïve NK cells from MHC-recombinant mice, as well as the MHC-I transgenic mice in which investigators utilized a single chain trimer (SCT) MHC-I molecule, SCT-Kb, that binds only one NK cell inhibitory receptor, Ly49C, on primary NK cells. In an SCT-Kb transgenic mouse deficient in KbDb- and 2m, only one MHC molecule (Kb) is expressed. Only Ly49C NK cells demonstrated an enhanced ability to produce IFN- as compared to NK cells from control mice (Kim et al., 2005; Yu et al., 2002). These studies lead to a concept of ‘licensing’, which states that, during development, NK cells need to be ‘licensed’ or ‘armed’ in the bone marrow to acquire a fully functional competence. In other words, maturation of the functional NK cells requires that their MHC-class-I–specific inhibitory receptors interact with self-MHC class I molecules, called ‘licensing’. These licensed NK cells are then allowed to be activated through their activation receptors. Failure to receive the licensing signal keeps NK cells in a hyporesponsive state (Kim et al., 2005). Licensing may explain why a lack of MHC-I expression does not demonstrate excessive NK cell activation. It also provides an explanation for hybrid resistance, which describes a phenomenon in which the NK cells from hybrid F1 mice reject the graft from either parent strain. In an F1 host that is heterozygous for MHC alleles, each MHC allele might potentially license different NK cell populations; therefore, an (A  B) F1 hybrid

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animal may have NK cells that are separately licensed on different MHC alleles. The NK cells that were licensed by MHC alleles from parent A are inhibited by A alleles but not B alleles, and thus reject bone marrow from parent B and vice versa. In the F1 animal itself, NK cells are licensed by either parental allele, so all NK cells should be inhibited by normal tissues that co-dominantly express both MHC alleles (Riley and Yokoyama, 2008).

Non-MHC-class-I–specific NK-cell recognition The recognition of MHC class I molecules is one of the critical features of NK cell recognition. However, in addition to the recognition of MHC class I molecules, NK cells also express receptors that are specific for a range of other ligands that are unrelated to MHC class I molecules. These ligands are widely expressed on the surface of normal cells, indicating an important role in self-tolerance.

Non-MHC-class-I–specific inhibitory receptors Several non-MHC-class-I–specific inhibitory receptors have been identified, such as carcinoembryonic-antigenrelated cell adhesion molecule 1 (CEACAM1), killercell lectin-like receptor G1 (KLRG1), NKR-P1A and NKR-P1B (Carlyle et al., 2004; Corral et al., 2000; Iizuka et al., 2003; Markel et al., 2004; Yokoyama and Plougastel, 2003), and some members of the Ly49-family (Table 47.1). 2B4 (CD244) is considered to be either an inhibitory or stimulatory receptor because of its ability to use different adaptor molecules to convey either inhibitory or stimulatory signals (Parolini et al., 2000; Roncagalli et al., 2005; Tangye et al., 2000). CD48 and 2B4 interaction may be a good example that provides another probable mechanism of NK cell tolerance in addition to MHC-dependent NK cell tolerance. Some studies observed an increased reactivity of NK cells that are deficient in MHC-I-specific receptors when 2B4 and CEACAM1 were blocked (Markel et al., 2004; McNerney et al., 2005), suggesting a potential role of these non-MHC-I–specific receptors in NK-cell self-tolerance. CD48 is expressed by human endothelial cells and all nucleated haematopoietic cells. It is a member of the CD2 family (Brown et al., 1998). Expressed by mouse and human NK cells, monocytes,  and  T cells, granulocytes and mast cells, 2B4 (CD244) belongs to the family of the signalling lymphocytic activation molecule (SLAM) (Boles et al., 2001; Kubota, 2002). Although mainly an activating receptor in humans, 2B4 is the inhibitory receptor for CD48. The density of 2B4 was noticed to be elevated 621

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at the surface of NK cells in a model that uses SH2-containing inositol phosphatase (SHIP)-deficient C57BL/6 mice. In this model, SHIP-deficient mouse NK cells do not express MHC-I–specific inhibitory Ly49 receptors, and the activation of these NK cells is suppressed by the inhibitory 2B4 receptor (Vaidya and Mathew, 2006). In addition, the inhibitory effects of the 2B4 receptors may contribute to the NK cell self-tolerance in a nonMHC-I–specific fashion to prevent NK cells from carrying out effector responses and attacking autologous cells. Of interest, NK cells from 2B4-deficient mice are more capable of eliminating CD48 tumour cells in vivo (Kubota, 2002; Vaidya et al., 2005). Some cytokines, such as IFN- produced by NK cells, were also shown to be downregulated, as well as their cytotoxicity (Lee et al., 2004). Similarly, the inhibitory receptor for cadherin KLRG1 usage was shown to be expanded significantly in NK cells lacking inhibitory self-MHC-I receptors or in MHC-I–deficient mice, while, in general, KLRG1 is expressed by relatively small population of NK cells (Corral et al., 2000). Thus, the absence of MHC-I–specific inhibition may be compensated by the acquisition of additional non-MHC-I–specific inhibitory receptors or their hyperactivity.

Achievement of self-tolerance without expressing inhibitory receptors specific for self-MHC class I molecules There are subsets of NK cells (such as the CI/NKG2 subset) that are deficient in all identified self-MHC-I–specific inhibitory receptors, but are still self-tolerant. Although they can display normal mature cell surface markers, such as CD11b, DX5, Ly49 receptors, and secrete proinflammatory cytokine IFN- upon stimulations in vitro with pharmacological agents or in vivo with Listeria monocytogenes, these NK cells do not respond in full strength to MHC-I–deficient normal cells or tumour cells, suggesting that self-tolerance can be achieved by attenuating stimulatory signalling. However, the hyporesponsiveness of the CI/NKG2 subset NK cells occurs only when their receptors are unable to bind self-MHC class I ligands as evidenced by the reactivity of these NK cells in MHC class I mismatched B10.M mice (Fernandez et al., 2005). Hence, these hyporesponsive NK cells are mature and functional, and play an important role in NK cell self-tolerance that can occur independently of MHC-I-specific inhibition.

ligands via antigen-specific receptors are deleted or rendered anergic. Although NK cells are not thought to undergo such selective processes, like T and B cells, NK cells also express activating receptors. A recent study demonstrated that NK cells might also undergo a selection process that would eliminate or inactivate NK cells that encountered a ligand during their development in bone marrow similar to T cell negative selection in thymocytes. NK cells bearing the DAP12-associated activating Ly49H receptor interact with the mouse cytomegalovirus (CMV)-encoded protein m157 on infected cells. In a specific pathogen-free mouse colony, immature NK cells should not encounter this viral ligand during development in the bone marrow. The Ly49H receptor has a high affinity for the viral glycoprotein m157 but does not recognize any self-antigen (Adams et al., 2007; Davis et al., 2008). These characteristics provide an opportunity to determine what happens to the immature Ly49H NK cells when they encounter m157 during development. To address this issue, the mice expressing m157 in the bone marrow were generated. The results showed that Ly49H NK cells were found in the periphery of m157-expressing mice; however, they were present at lower numbers, less mature, produced less IFN- and were severely defective in their ability to mediate cytotoxicity and proliferate in response to mouse CMV infection, indicating that if immature NK cells encounter ligands for their activating receptors during their development, regulatory mechanisms exist to keep these cells in an hyporesponsive state (Sun and Lanier, 2008; Tripathy et al., 2008). Repeated antigenic stimulations are known to induce expression of several inhibitory receptors, including KIR on immune cells (McMahon and Raulet, 2001).

NK cells in regulation of immune responses NK cells are key innate effector cells in eliminating viruses, tumour and hazardous cells by direct killing before the onset of adaptive T and B cell immunity. Their in vivo importance has been demonstrated by studying NK-cell–deficient patients and mouse models. Dysfunction or depletion of NK cells results in frequent and severe infections (Gazit et al., 2006). Recent data implicate more complex roles for NK cells. They also participate in regulation of immune responses via interacting with various immune components.

Continuous engagement of activation receptors induces NK cell tolerance

NK and dendritic cell interaction

During development, T and B cells undergo selection, that is, those T and B cells encountering their cognate

Mouse cytomegalovirus infection models demonstrated preferential distribution of IFN NK cells near marginal

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zone areas of secondary lymphoid organs, where antigenpresenting cells (APC), mostly dendritic cells (DC), accumulate and prime T cells, suggesting the influence of NK cells on APC–T cell crosstalk (Daniels et al., 2001). Much attention has been given to the interactions between NK cells and DC. Indeed, NK cells interact intimately with DC, which has important implications for ensuing links of innate and adaptive immune responses. During the interactions, the two types of cells form an immune synapse with each other. The physical contact between NK and DC involves interactions among several receptor–ligand pairs, which include LFA-1, NKp30, NKp46, 2B4, DNAX accessory molecule 1 (DNAM-1), NKG2D, TNFRII and NKG2A (Xu et al., 2007). NK cells induce secretion of IL-12, IL-18 and membrane-bound IL-15 from DC. These cytokines in turn activate NK cells to secrete IFN-, TNF- and high mobility group box-1 (HMGB1), which cause DC maturation (Zitvogel, 2002). Conversely, CD8 DC were shown to induce selective expansion of NK cells in vivo through secretion of IL-12 and IL-18 (Degli-Esposti and Smyth, 2005). Another study demonstrated that NK cells were induced by DC to function as non-cytotoxic ‘helper’ cells following stimulation with IL-18, which facilitated IFN secretion from NK cells and thus enabled DC to secrete IL-12p70, leading to Th1 polarization (Degli-Esposti and Smyth, 2005). An indirect role for NK cells in priming the Th1 CD4 T cell response by providing IFN- in the lymph nodes has also been shown in vivo. Injection of mature DC with adjuvant led to CXCR3-dependent recruitment of NK cells to the lymph nodes, where they provided an initial source of the IFN- necessary for Th1 polarization. Depletion of NK cells resulted in a reduced Th1 response and was dependant on IFN- production from NK cells (Mailliard et al., 2005; Martin-Fontecha et al., 2004). On the other hand, it has been well established that NK cells can effectively regulate DC functions by inducing DC lysis shown in co-culture of human NK cells with autologous DC (Scott and Trinchieri, 1995; Unanue, 1997). NKp30, DNAM-1 (CD226, a co-stimulation and adhesion molecule), and LFA-1 molecules are involved in the NK cell-mediated killing of autologous, immature DC (Ferlazzo et al., 2002). However, mature DC can escape from killing, as the maturation process induces expression of human leukocyte antigens (HLA) antigens, which protect them from NK cells. NK cells can influence immature DC leading either to their maturation or to death in vivo. This is largely dependant on the interaction between the NKp30 receptor and an unknown ligand that is expressed on the surface of immature DC (Ferlazzo et al., 2002). The CD56highCD16dim NK cell subset interacts with immature DC and drives maturation or kills the immature DC. These NK cells express little KIR, but express CD94/NKG2A as the main inhibitory receptors. It remains unclear how NK cells choose

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between killing and causing maturation of immature DC. It probably depends on the profile of expression of several molecules on the surface of immature DC. If DC fail to express HLA antigens upon maturation, they may be killed by NK cells. The ratio between NK cells and their interacting DC is also a factor: A greater ratio tends to favour killing rather than maturation. A recent study reported that when activated human NK cells were cultured with immature DC in vitro, at low NK/DC ratios (1:5), NK cells were able to significantly induce DC maturation and cytokine secretion and therefore cause DC activation. Cell-to-cell contact and endogenously produced TNF- in the culture are required for DC maturation induced by NK cells. In contrast, at higher NK/DC ratios (5:1), DC functions were completely inhibited due to the effective killing by the autologous NK cells, implicating a potential role of contact-dependent NK–DC interactions in the regulation of the immune response (Piccioli et al., 2002). NK cells stimulated by IL-2 increased their cytotoxicity, and enhanced immature DC killing activity, whereas, exposure to IL-18 did not affect NK cell cytotoxicity and DC killing. This supports the notion that the functions of NK cells as ‘effector’ and ‘helper’ cells represent two independent mechanisms that might be controlled through separate pathways (Unanue, 1997). The interplay between NK cells and DC has been also investigated in models of bacterial infection. In one study, immature DC underwent maturation when they were cultured in the presence of Escherichia coli or Bacillus Calmette–Guérin. Upon infection, production of considerable amounts of TNF- and IL-12 were detected, whereas IL-2 and IL-15 were hardly detectable in supernatants. After NK cells and DC were cultured together for 24 h, HLA class I molecule expression was upregulated on the surface of the bacteria-infected DC. These infected DC were more resistant to NKmediated killing. The NK cells that were exposed to bacteria-infected DC were then activated and became capable of killing autologous immature DC. This study demonstrated that DC-induced NK cell activation can be significantly enhanced by the presence of pathogens and thus may regulate subsequent innate and adaptive immune responses (Ferlazzo et al., 2003). An in vivo DC-based vaccine study demonstrated a rapid elimination of immature DC by NK cells through a pathway dependant on the TNF-related apoptosisinducing ligand (TRAIL). In addition, during immunization with immature DC loaded with foreign or tumour antigens, when NK cells were depleted and/or TRAIL function was neutralized, T cell responses to these antigens were enhanced. Therefore, responses to DC-based vaccination may be determined and regulated by the survival of antigen-loaded DC, which is controlled by TRAIL on NK cells (Hayakawa et al., 2004). 623

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NK and T cell interaction Human NK cells efficiently enhance CD4, as well as CD8 T cell proliferation in response to antigen-specific or anti-CD3 stimulation. This process depends on direct contact-mediated interactions mainly between costimulatory molecules expressed on NK cells (including CD80, CD86, CD70, OX40 ligand and 2B4 receptors) and their counterparts expressed on T cells (e.g. CD28, CD27, OX40 and CD48) (Hanna et al., 2004a,b, 2005; Zingoni et al., 2004). Activated human NK cells express MHC class II and have the capability to present antigens directly and stimulate CD4 T cell proliferation in vitro (Hanna et al., 2004); therefore, activated human NK cells possess not only the required co-stimulatory molecules for potential interaction with activated CD4 T cells, but also have the capacity to process and present antigens through MHC class II. Although DC are considered to be the most potent APC, the fact that activated NK cells express MHC class II, CD86, CD80, CD70 and OX40L strongly suggests the possibility that they might also communicate directly with CD4 cells. However, it is difficult to provide convincing evidence of this interaction in vivo in humans due to obvious limitations. Interestingly, activated mouse NK cells do not express MHC class II; therefore, the mouse is not an appropriate model to examine MHC class II TCR-dependent CD4 cell interactions with NK cells (Zingoni et al., 2004). The role of NK cells in CD8 T cell effector function was examined in the situation of intracellular Mycobacterium tuberculosis infection. CD8IFN- cells are normally able to effectively lyse M. tuberculosisinfected monocytes in the presence of NK cells. However, the killing capacity and the frequency of M. tuberculosisresponsive CD8IFN- cells were decreased when NK cells were removed from peripheral blood mononuclear cells (PBMC) of healthy tuberculin reactors. IFN-, IL-15 and IL-18 were secreted by M. tuberculosis-activated NK cells; they are the key cytokines to facilitate the restoration of CD8IFN- cell frequency. Activated NK cells also stimulated M. tuberculosis-infected monocytes to produce IL-15 and IL-18 that in turn promote the expansion of CD8 T cells. Cell–cell contact between NK cells and M. tuberculosis-infected monocytes was required and the CD40–CD40 ligand interactions were important for NK cells to maintain the capacity to prime CD8 T cells. By connecting innate and adaptive immune responses, NK cells can optimize the capacity of CD8 T cells to execute their effector response and to protect against pathogen invasion (Vankayalapati et al., 2004). Several studies have demonstrated that NK cells have the ability to regulate CD4 and CD8 responses. In a gender-dependent model of preferential Th1 and Th2 activation, NK cells influenced CD4 T cell activation and regulated adaptive immunity prior to antigen exposure. 624

This model utilizes the Swiss Jim Lamert (SJL) mice that exhibit a gender-dependent differential response to immunization. In this model, young adult male SJL mice were normally unable to activate Th1 cells. However, by depletion of NK cells, the activation of Th1 effectors was permitted in males (Dowdell et al., 2003).

NK cells in transplantation Although NK cells play a crucial role in rejection of bone marrow transplants (Ruggeri et al., 2002), only recently, it has been noted that NK cells may also participate in the rejection of solid organ grafts (Beilke and Gill, 2007; Kitchens et al., 2006). Essential features of NK cells in transplantation include distinguishing allogeneic cells from host and their effective cytolytic effector responses. The interaction between NK cells and host adaptive immune system (DC and T cells) also play an important role in allogeneic transplantation. The rejection of solid organ transplants is often associated with heavy infiltration by NK cells. NK cells that infiltrated in rat liver allografts were responsible for production of early chemokines, as well as cytolytic granzyme A and B, keys to an acute rejection episode (Illes et al., 2000). Depletion of NK cells prolonged the allograft survival in CD28/ recipients. Thus, NK cells may participate in rejection by facilitating the action of alloreactive cells (Gerosa et al., 2002). In human liver transplants, a correlation between acute rejection episodes and donor– recipient KIR mismatches was discovered (Russell and Ley, 2002). In addition, NK cells also mediate chronic allograft vasculopathy in a T-cell–dependent manner (Uehara et al., 2005). Some studies have suggested that NK cells may also promote transplant tolerance, but the mechanism is not clear as to how these cells of the innate immune response regulate the adaptive T-cell response in transplant-tolerance models (Gasser and Raulet, 2006). A recent report, using skin allografts in the Rag/ mouse model, showed that in the absence of NK cells, donor-derived APC survived and migrated to the host lymphoid nodes where they directly stimulate the activation of alloreactive T cells. In the absence of NK cells, a co-stimulatory blockade-mediated graft survival was difficult to achieve. This was associated with large amounts of donor APC detected. Whereas, the donor APC were almost completely absent in the presence of NK cells, indicating that NK cells are able to induce transplant tolerance by killing donor APC, which can inhibit priming of alloreactive T cells (Yu et al., 2006). Activated NK cells are indeed capable of killing autologous immature DC. It is possible that NK cells may also influence indirect antigen presentation by killing immature host DC or DC that are mature, but express low MHC class I molecules, resulting in inhibition of

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the activation of T-effector cells or interfere with the induction of regulatory T cells (Kroemer et al., 2008). NK cells can also enhance allograft tolerance following direct interaction with alloreactive T cells. Induction of islet allograft tolerance induced by either anti-CD154 or anti-LFA-1 required intact perforin-mediated cytolytic activity of NK cells. NK cells promoted allograft tolerance by eliminating activated alloreactive T cells through a perforin-dependent mechanism (Beilke et al., 2005). NK cells are also able to regulate adaptive immune responses by directly inhibiting clonal expansion of activated T cells in an autoimmune disease model (Singh et al., 2001). Taken together, both APC and alloreactive T cells can be targets by NK cells in the induction of transplant tolerance. It remains unclear whether the tolerogenic effect is attributed to a specific subset of NK cells. The involvement of antigen-presenting property of NK cells also requires further investigation.

NK cell tolerance and viral infection Although viral infection activates NK cells, viruses also use multiple strategies to manipulate the response and to achieve chronic persistence (Figure 47.2). NK cell functions (killing of target cells, ADCC effector function, editing of DC and production of cytokines and chemokines) become defective during viral infection. The defects in the NK cell compartment usually occur in the early stages of infection (Iannello et al., 2008).

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How does viral infection result in impaired killing activity of NK cells? The role of cell adherence molecules, conjugate formation, and polarization of cytotoxic granules is crucial for NK cell-mediated killing. In viral infections, shedding of soluble ICAMs and CD16 is increased in the circulation. The soluble forms of these adhesion molecules interfere with their membrane-inserted forms, resulting in compromised killing activity of NK cells since NK cells, due to an impaired ability to form immune synapses with target cells. The HIV protein Tat inhibits NK cell-mediated lysis by blocking L-type Ca channels because Ca influxes are crucial for activation of calcium/calmodulin-dependent protein kinase (CaMK)-II rearranging microtubules in NK cells following activation (Zocchi et al., 1998). Although NK cells from HIV infected patients form conjugates with target cells, they are defective in triggering cytolytic activity for infected targets (Bonavida et al., 1986). Interestingly, the defect in NK cells from virally infected individuals may reside in establishing a structure for triggering cytolytic activity. In addition, the number of NK cells is also decreased over time in chronic viral-infected patients, particularly, the CD8CD16 and CD56CD16 NK cell subpopulations. This is often accompanied by an increase in CD16CD56 NK cells that are known to express KIR, a functionally defective subpopulation. It has been demonstrated that the CD16CD56 subset of NK cells expand in primary viral infections. Moreover, NK cells from viral-infected patients express

Figure 47.2 l NK tolerance is induced by viruses via multiple strategies. The virus-derived proteins/peptides (1) increase MHC class I gene expression and/or biosynthesis; (2) enhance the expression of inhibitory and/or decrease the expression of activating receptors on the surface of NK cells of the infected host; (3) can also modulate expression of non-classical MHC antigens. The inhibitory signal counters the stimulatory signals so that the NK cell is rendered inactive and the infected cell escapes NK killing.

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lower levels of perforin and higher levels of SHIP, which may be responsible for their poor cytolytic and activating potentials (Alter et al., 2006). Some viruses can also produce bioactive factors, including proteins and derived peptides, that possess NK cell inhibitory properties, although the exact mechanism of inhibition of the peptides remains unknown (Alter et al., 2006). Viruses can use other strategies to counter NK cell responses of the host. NK cell function is largely regulated by the balance of inhibitory and activating receptors. The inhibitory receptors recognize primarily MHC class I molecules, while the activating receptors recognize stress-induced ligands and viral products. Changes in the ligation of the inhibitory and activating receptors will affect the outcome of the target cells. Rapid responses of NK cells to infections may lead to efficient control of pathogen replication, while in addition to tolerance recognition, may allow for the persistence of pathogens. The down-regulation of MHC class I antigens on the surface of infected cells is a common strategy used by a variety of viruses to evade antiviral cytotoxic T lymphocyte (CTL) responses of the host, as CTL recognize viral peptides in association with these antigens (Iannello et al., 2008). For instance, upon influenza virus infection, the viral haemagglutinin (HA) protein is recognized by two NK activating receptors, NKp44 and NKp46, and this recognition leads to enhanced killing by NK cells (Arnon et al., 2004; Gazit et al., 2006). Following influenza virus infection, the binding of the two NK inhibitory receptors, KIR2DL1 and the LIR1, to the infected cells is increased, prior to the increased recognition of activating receptor, NKp46. In elucidating the mechanism responsible for this effect, MHC class I proteins were found to redistribute on the cell surface and accumulate in the lipid raft microdomains following influenza virus infection. Such redistribution allows for better recognition by the NK inhibitory receptors and consequently increases resistance to NK cell attack, suggesting that the influenza virus can escape NK cell cytotoxicity via enhancing reorganization of MHC class I on infected cells (Achdout et al., 2008). Several HIV proteins have also been shown to affect expression of MHC class I antigens: Tat antigen represses promoters of the MHC class I and the -2 microglobulin genes, and the viral protein U (Vpu) interferes with an early step in the biosynthesis of MHC antigens. The viral protein Nef can also recognize certain motifs present in the cytoplasmic tails of MHC class I antigens and cause their degradation (Bonaparte and Barker, 2004). In addition to classical MHC class I antigens, HIV can also modulate expression of non-classical MHC antigens. HIV infection increases the expression of HLA-E on the surface of CD4 T cells. One potential mechanism of this increase is a peptide from the viral protein p24 (residues 14–22), which can bind and stabilize HLA-E on the surface of 626

HIV-infected cells. An increased expression of HLAE has been reported on the surface of CD4 T cells in HIV-infected persons, and the increase was more pronounced in advanced stages of infection and correlated with peaks in viraemia (Martini et al., 2005). In addition, viruses can evade innate immune responses by increasing their expression of inhibitory and/or by decreasing the expression of activating receptors on the surface of NK cells of the infected host. HIV may use this strategy to counter antiviral NK cell responses. Several studies have shown an increase in the expression of NK cell inhibitory receptors, such as KIR, and a decrease in the expression of activating receptors, such as NCR, in HIV-viraemic patients, which was correlated with viral load, and was often accompanied with decreased cytolytic activities of NK cells (Eger and Unutmaz, 2004) (see Chapter 36). This is supported by data showing that long-term administration of highly active antiretroviral therapy (HAART) results in undetectable viral loads and is associated with restored expression of the receptors on NK cells (Mavilio et al., 2003). Viruses may also target NK cell–DC interactions for immune evasion. Activated NK cells from viraemic patients are unable to kill autologous, immature DC (Mavilio et al., 2003). This defect was more profound in the CD56CD16 NK cell subset, even after masking NK cell inhibitory receptors. The mature DC from HIV-infected patients produced less IL-12 and could not activate NK cells with which they where interacting. Consequently, these NK cells produce less IFN-. Defective NKp30- and TRAIL-mediated killing was attributed to the escape of the immature DC from NK cell-mediated killing in HIV-infected persons (Mavilio et al., 2006). Nef also affects DC and NK interactions. Nef-pulsed DC inhibit chemokine secretory capacity as well as the cytotoxic ability of NK cells by inducing TGF- and IL-10 (Quaranta et al., 2007).

NK cells and maternal tolerance The maternal–foetal interface is a site in which foetalderived trophoblast cells invade into maternal uterine tissue that contains many immune cells (see Chapter 30). Over 85% of these cells are NK cells with maternal CD56bright CD16, but not CD56dim CD16, phenotype, whereas other immune cells are sparsely found (Croy et al., 2003). As is well known, the proper trophoblast invasion into maternal uterine spiral arteries and decidua is critical for optimal placentation and thus reproductive success. Failure to achieve this invasion may result in reproductive complications and a poor outcome. Depletion of decidual NK (dNK) cells in mice resulted in changes in the development of blood vessels early after implantation. dNK cell-derived IFN- is responsible for facilitating growth of blood vessels during

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decidualization (Ashkar and Croy, 1999, 2001). Indeed, invasive foetal trophoblasts are involved in attracting CD56bright NK cells through production of a distinct set of chemokines (mainly stromal cell-derived factor-1 and macrophage inflammatory protein-1), suggesting that the maternal CD56bright NK cells are actively recruited by foetal trophoblast cells to populate the decidua in normal pregnancy (Hanna et al., 2003). The interesting enigma of pregnancy is that the foetal cells are actually allografts to the maternal immune system but, in normal pregnancy, they are not rejected. dNK cells reside very close to foetal trophoblast cells of the placenta, which would seemingly lead to catastrophic consequences, because the trophoblast cells are semi-allogeneic. Many studies have tried to characterize why and how these NK cells do not exert cytolytic functions. Although the dNK cells express the essential machinery required for lysis, including perforin, granzymes A and B, their cytotoxic activity is reduced compared with peripheral blood NK or NK present in non-pregnant endometrium (Bogovic et al., 2005; Bulmer et al., 1991). However, dNK cells in vivo do not kill foetal-derived trophoblast cells. dNK cells generally express NKp30, NKp44, NKp46, NKG2D and 2B4 activating receptors, but only a few of the dNK cells express the CD160 activating receptor (Kopcow et al., 2005; Rabot et al., 2005). CD160 is a marker of cytotoxicity. During normal pregnancy, the majority of dNK cells are not cytotoxic to target cells (Tabiasco et al., 2006). dNK cells cannot kill trophoblast cells efficiently in vitro unless activated by IL-2, a cytokine not normally found in gestational endometrium (Avril et al., 1999; Loke et al., 1995; Sivori et al., 2000). Inhibition of cytotoxicity of dNK has also been proposed due to the interaction of HLA-G, HLA-E and/or HLA-C expressed by extravillous cytotrophoblast with their inhibitory receptors, ILT2, CD94/NKG2A, and KIR, respectively (Avril et al., 1999). Absence of killing of trophoblast cells by dNK could also be due to the high levels of the active form of X-linked inhibitor of apoptosis (XIAP) in the trophoblast. This potent caspase inhibitor downregulates the Fas apoptotic cascade in the trophoblast during early pregnancy (Straszewski-Chavez et al., 2004). Pre-eclampsia is a complication of pregnancy characterized by hypertension and proteinuria, which is a major cause of maternal and foetal mortality. The exact cause of pre-eclampsia is unclear but a hallmark of pre-eclamptic pregnancies is the suboptimal invasion of trophoblast cells in the uterus and spiral arteries leading to poor restructuring of the blood supply (Pijnenborg et al., 2006). Several dNK cell receptors interacting with foetal HLA alleles may result in proangiogenic growth factor production by the dNK cells, which in turn affects the degree of trophoblast invasion, spiral artery remodelling and thus the overall quality of placentation. A strong maternal KIR

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and foetal HLA-C inhibitory signal predispose to preeclampsia (Trowsdale and Betz, 2006). Recurrent spontaneous abortion (RSA) affects about 1% of pregnancies. Immune response may play a role in some cases. Thus, some women with unexplained RSA display increased numbers of CD56dimCD3 CD16 dNK cells (Quenby and Farquharson, 2006). Women with RSA demonstrate a restricted repertoire of MHCI–specific inhibitory receptors with relatively fewer inhibitory KIRs specific for HLA-Cw alleles expressed by the foetus (Varla-Leftherioti et al., 2003, 2005). However, some women with RSA also demonstrate increased numbers of MHC-I–specific activation receptor genes (Wang et al., 2007).

Breaking NK cell tolerance for cancer therapy NK cells stand on the frontier of novel therapeutic agents against tumour growth and metastasis. Since a balance of signals from activating and inhibitory receptors determines the reactivity of NK cells, it is essential to maintain NK cell self-tolerance without compromising its reactivity against transformed tumour cells. Induction of ligands for NK cell activating receptors often occurs during transformation on tumour cells, therefore providing a way to differentiate them from normal self cells. Upregulation of the ligands for activating receptors may also result in increased NK cell susceptibility. This was demonstrated by more efficient rejection of RMA-S lymphoma cells (that possess a defect in class-I assembly and express markedly reduced levels of class-I molecules at the cell surface) by NK cells in vivo (Oberg et al., 2004). In addition, MHC-I–specific NK recognition is an important facet in regulating NK development of NK cell reactivity and tolerance. The models discussed earlier in this chapter suggest that NK cells can be ‘educated’ during their maturation process and development. Thus, could NK cells be manipulated during the development and be ‘tuned’ to optimally sense the absence of self-MHC class I? The use of NK cells in breaking tolerance to tumours may have considerable implications in the treatment of patients with cancer. An increased cytotoxicity to tumour cells and decreased progression of syngeneic leukaemia was shown when MHC-I–specific Ly49 inhibitory NK cell receptors were blocked with F(ab)2 fragments of 5E6 monoclonal antibody. This study supports a potential role of using blockade to NK cell inhibitory receptors as an efficient immunotherapy for cancer (Koh et al., 2001). Recent clinical data have shown that in patients with acute myeloid leukaemia, the use of KIR–ligand mismatch in a HLA-mismatched stem cell transplantation setting generated remarkable 627

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graft-versus-leukaemia effect and significantly decreased the relapse rate in these patients as well as improving their overall survival. Donor NK cells may exert their potent anti-leukaemic effector response in the host via missing-self-recognition (Plunkett and Ellis, 2002; Ruggeri et al., 1999). CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1 [CD66a]), an inhibitory receptor expressed by NK cells, mediates immune self-tolerance in a non-MHC-I–specific fashion. The ligand for CEACAM1 is CEACAM1 itself. It is expressed at higher levels in multiple types of malignancies, such as in colon, prostate, breast, and endometrial cancer (Thies et al., 2002). CEACAM1 can also be

expressed by cells in malignant melanoma, in which its increased expression correlates with increased metastasis (Thies et al., 2002), thus indicating a poor prognosis (Markel et al., 2002). CEACAM1 has many roles in carcinogenesis. It was found to inhibit the anti-tumour activity of NK cells in vitro (Gerosa et al., 2002; Illes et al., 2000), but demonstrated other features in vivo, such as the ability to promote angiogenesis and metastasis, and tumour-suppressor activity (Plunkett and Ellis, 2002). Thus, modulation of non-MHC-I– specific receptors such as CEACAM1, may be another potential means for the immunotherapy of patients with cancer.

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