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BEYOND REASON
NK 세포활성도를 검사하여 활용방안 찾기!!
Natural killer cells represent a highly specialized lymphoid population with a potent cytolytic activity against virus-infected or tumor cells. Their function is regulated by a series of inhibiting or activating signals. The mechanisms by which NK cells kill susceptible target cells was thought to be elucidated after the discovery of inhibitory receptors specific for MHC-class I molecules: NK cells would kill those target cells that lack MHC-class I molecules. However, the actual scenario revealed more complex with the discovery of activating receptors and their ligands. Thus, in certain pathological conditions, corticosteroid treatment or exposure to TGF, NK cells may under-express activating receptors. In addition, target cells may lack ligands for activating receptors and thus fail to activate NK cells upon cell-to-cell contact. This clearly implies that activation of NK cells and of their potent effector mechanism are under the control of different checkpoints.
© 2005 Elsevier B.V. All rights reserved.
1. Introduction
Natural killer cells play an important role in innate immu- nity as they are characterized by strong cytolytic responses against tumor or virus-infected cells and by their ability to release cytokines and chemokines that mediate inflamma- tory responses to induce hematopoiesis and modulate the subsequent adaptive immune responses [1–3]. Despite their relevance in defense mechanisms, major questions regard- ing their mode of action and their precise nature had long remained unanswered. However, this has rapidly changed in recent years and we have now a fairly accurate perception of the general mechanisms that regulate NK cell activation and function [4,5]. Indeed, the general molecular strategies that allow NK cells to spare normal cells and kill tumor or virally infected cells have now been unravelled thanks to the identification of various surface NK receptors con- tributing to the process of NK cell activation or inactivation [5–7]. Increasing experimental evidence supports the notion that NK cell activation and function are under the control of different checkpoints, the role of which is to prevent the inappropriate triggering of destructive effector mecha- nisms and to allow NK cell activation only when necessary [8].
2. NK cell inactivation: interaction between MHC-class I and MHC-class I-specific inhibitory receptors
In the early 1990s, parallel studies in humans [9–11] and mice [12] revealed that NK cells recognize major histo- compatibility complex (MHC) class I molecules via surface receptors that deliver signals that inhibit NK cell cytotoxi- city. Accordingly, when these receptors fail to interact with MHC-class I molecules, killing of target cells may take place [13]. This occurs when target cells have lost or under-express MHC-class I molecules [14]. Accordingly, two related check- points are represented by the surface expression of MHC- class I molecules on target cells and by the expression of specific inhibitory receptors on NK cells.
2.1. Surface expression of HLA-class I molecules on target cells
In an autologous setting, the expression of MHC-class I molecules on potential target cells represents the best-known checkpoint in the control of NK cell activation [8]. The failure to express one or more MHC-class I alleles might represent a major threat to host integrity as both viral infection and tumor transformation could induce MHC-class I downregulation [15,16]. In this context, certain cytopathic viruses, including herpes viruses and adenoviruses have developed strategies to escape the control exerted by HLA-class I-restricted CTL [17,18]. For example, human cytomegalovirus (CMV) codes for different “unique short” (US) proteins that inhibit the
expression of HLA-class I molecules at the surface of infected cells [17,19,20]. Accordingly, NK cells play a crucial role in the host defenses against CMV (and other herpes viruses). Remarkably, NK cells are likely to play a more general pro- tective role in viral infections, particularly in their early stages when CTLs are unable to mediate protection. It is conceiv- able that, in the course of viral infection, various peptides might be generated that bind different HLA-class I alleles and prevent their recognition by specific KIRs, resulting in target cell lysis [21]. These might represent a general mech- anism by which NK cells limit virus spreading during the early phases of infection.
Regarding the HLA-class I expression in tumor cells, these often express low levels of these molecules. In this context, as reported by Garrido et al. [15] over 85% of human metastatic carcinomas display deficient HLA-class I expression. This could reflect a loss of a single allele, of one full haplotype of a given HLA-class I locus. Tumor cells might also be characterized by a general downregu- lation of all class I alleles. In this case, a partial restoration of HLA surface expression (and increased resistance to NK cell-mediated lysis) can be induced in vitro by interferon- [22].
2.2. Surface expression of MHC-class I specific inhibitory receptors
In humans, killer-Ig-like receptors (KIR) and CD94- NKG2A play a major role as HLA-class I-specific inhibitory receptors (iNKR) in human NK cells [13,23]. KIR, are encoded by a diverse and rapidly evolving family of genes [24–26]. Different individuals differ in the number and type of inherited KIR genes. Thanks to the differential expression of KIR and CD94-NKG2A genes, human NK cells gener- ate diverse repertoires, each NK cell being characterized by at least one inhibitory receptor for autologous HLA-class I molecules. Since KIRs recognize allelic specificities of HLA- class I molecules, their clonal distribution allows the whole NK cell pool to sense the loss of even single alleles in tumor or virus-infected cells [13,27]. As a consequence, both the direct killing of HLA-class I deficient cells and the release of pro-inflammatory cytokines or chemokines can provide an efficient and rapid first line of defense against major threats [2,28].
It is of note that, in the early stages of their maturation in the bone marrow (BM), human NK cells do not express iNKR, while they do express activating receptors and an effi- cient cytolytic machinery [29]. Why do these immature NK cells do not kill bystander BM cells? A likely explanation has been proposed that involves a fail-safe mechanism mediated by 2B4 molecule. 2B4, together with NTBA, are members of the CD2 family, serve a dual, inhibitory or activating, function depending on the availability of downstream reg- ulating elements in their signaling pathway [30,31]. Their cytoplasmic portion binds a small cytoplasmic protein termed signaling lymphocyte activation molecule-associated protein (SAP) and delivers triggering signals leading to NK cell acti- vation. The absence of SAP, a molecular defect typical of X- linked lymphoproliferative (XLP) disease, results in binding of SHP-1 phosphatase to 2B4. The consequent SHP-1 activa- tion leads to inhibition of the activation pathways thus block- ing NK cell function [32]. Interestingly, 2B4 is expressed at the earliest stages of hemopoietic stem cell differentia- tion, while SAP transcripts are absent [29]. Accordingly, 2B4 cross-linking by specific mAbs or by its ligand CD48 inhibit the function of immature NK cells. Remarkably, CD48 is expressed at high densities in bone marrow cells. Thus, it is conceivable that 2B4 can provide an effective fail-safe mech- anism to prevent NK cell-mediated damages to bone marrow cells.
With the remarkable exception of immature NK cells (see above), NK cells normally express receptors that allow recognition of self HLA-class I molecules thus preventing possible NK cell triggering upon interaction with normal cells. The situation can be rather different in an allogeneic setting, involving NK cells and mismatched target cells. A paradigmatic example is represented by the haploidentical bone marrow transplantation, in which only one of the HLA- carrying chromosomes is matched, while the other is fully mismatched [33]. This always occurs with parents as bone marrow donors. Under these conditions, a KIR-HLA-class I mismatch might be present so that a fraction of donor’s NK cells might express KIRs that do not fit with the HLA- class I alleles of the patients [34]. Haploidentical BMT has been attempted when no BM from HLA-class I-compatible donors was available. High numbers of CD34+ cell pre- cursors that had been extensively depleted of T cells (to avoid severe GvHD) are infused. NK cells develop from such CD34+ cells shortly after engraftment and represent the only lymphoid population detectable in the peripheral blood for several weeks. The “alloreactive” NK cells have the poten- tial to kill leukemic cells and other lymphohemopoietic cells of the patient including residual lymphocytes, DC and their precursors [35,36]. This might explain while in haploidenti- cal BMT, neither GvHD nor graft rejection occur. Remark- ably, alloreactive NK cells do not cause themselves GvHD. This is likely to reflect the fact that normal, nonactivated cells of non-hemopoietic origin do not express or express low densities of the ligands of activating NK receptors (see below).
3. NK cell triggering: activating NK receptors and their cellular ligands on target cells
Since turning NK cell “off” represents the major fail-save mechanism to prevent the NK-mediated attack to normal HLA-class I+ autologous cells, an “on” signal must be gener- ated upon interaction of NK cells with potential target cells. This signal is extinguished whenever appropriate interac- tions occur between inhibitory receptors and MHC-class I molecules [4].
3.1. Surface expression of activating NK receptors in NK cells
The receptors involved in NK cell triggering during the process of natural cytotoxicity remained elusive until recent years, when three novel surface molecules were identified and molecularly characterized. Collectively termed natural cyto- toxicity receptors (NCR) [37,38], NKp46 [39,40], NKp30 [41] and NKp44 [42,43] represent the prototypes and the most important receptors involved in the lysis of different tumors (Table 1). They possess limited homology with known human molecules and no homology each other. Their surface density on NK cells correlates with the magnitude of the cytolytic activity against susceptible target cells (see below) [41,44]. Since the surface expression of NKp46 and NKp30 is restricted to NK cells, they represent the most reliable mark- ers for NK cell identification. NKp44 is de novo expressed on activated, IL-2 cultured NK cells, a finding that might explain the higher levels of cytolytic activity of activated NK cells cultured in IL-2. Another activating receptor that plays a role in lysis of various tumors is represented by NKG2D, charac- terized by a lectin-like domain [45]. NKG2D is not restricted to NK cells, but is also expressed by cytolytic T lymphocytes. NKG2D is specific for the stress-inducible MICA, MICB or ULBP proteins (Table 1) [46–51].
Other triggering surface molecules expressed by NK cells (but shared by other leukocytes) appear to function pri- marily as co-receptors, that is, their capability of signaling mostly depends on the simultaneous co-engagement of one or another triggering receptor [38]. They could function pri- marily by amplifying the signal delivered by true receptors. In addition to 2B4 and NTBA (see above), other triggering coreceptors have recently been identified including DNAM- 1, NKp80 and CD59 (Table 1) [52–54].
In most donors, mature NK cells express normal levels of activating receptors and coreceptors. However, a remarkable exception is represented by a small fraction (<10%) of oth- erwise normal individuals who are characterized by variable fractions of their NK cells expressing an NCRdull phenotype. This NK cell phenotype is substantially stable over time and results in impairment of the ability to kill those target cells that are primarily lysed via NCRs [41,44]. While one could spec- ulate on the possibility that these individuals might display an increased susceptibility to certain tumors, it should be noted that the NCRdull phenotype is actually confined to a subset of NK cells. Thus, the impaired function of some NK cells can be compensated by other NK cells expressing an NCRbright phenotype.
Importantly, under different pathological conditions [55,56], drug treatment [57] or exposure to cytokines in vitro [58], a marked decrease of the surface expression of activat- ing receptors has been detected.
A remarkable finding was that the uniformly NCRdull phe- notype is present in over 90% of patients affected by acute myeloid leukaemia (AML) [55]. Because lysis of AML is pri- marily dependent on NCR and does not involve NKG2D, an important consequence is that NK cells from AML patients do not kill autologous leukemic cells. A relevant implication of these data is that autologous NK cells cannot be employed in protocols of adoptive immunotherapy. In contrast, as dis- cussed above, allogeneic “alloreactive” NK cells are efficient and can kill leukemic cells both in vitro and in vivo (in the haploidentical BMT setting) [33].
Although less pronounced, downregulation of NCR has been observed in HIV+ viremic patients [56]. Following treat- ment with effective antiviral treatment, the expression of NCR returned to normal values. A strong inhibition of the sur- face expression of NKp30 and, in part, of NKG2D has been detected in vitro upon exposure of NK cells to TGF [58]. Finally a sharp downregulation of NCR surface expression has also been detected upon NK cell exposure to corticos- teroids both in vitro and in patients treated with these drugs [57].
3.2. Expression of ligands of activating NK receptor
The “on” signal leading to NK cell activation requires the engagement of activating receptors with specific lig- ands expressed on target cells. Accordingly, the presence or absence of ligands will provide an important checkpoint in the NK cell activation and tumor cell lysis [5]. The direct demonstration of such ligands on target cells is limited, since only some of them have been identified while those recog- nized by NCR remain to be identified. Two groups of ligands of activating receptors have been identified so far by the use of specific mAbs. An important information has emerged from these studies, i.e. that these ligands are either lacking in nor- mal cells or expressed in particular cell sites not accessible to NK cells (e.g. the intercellular junctions in endothelial or epithelial cells) or expressed in insufficient surface den- sity to allow NK cell triggering. Analysis of the ligands of NKG2D, i.e. the stress inducible MICA and MICB or ULBP, allows to determine whether or not they are expressed at the surface of target cells [49–51]. This information, in turn, allows to predict whether a given target cell will be sus- ceptible to NK cell-mediated lysis. Extensive studies have been performed on melanomas, lymphomas and leukemias. The NK-mediated lysis of those tumors that expressed NKG2D ligands could be inhibited by mAbs specific for
NKG2D. However, frequently, lysis could not be abrogated [59].
A partial inhibition was obtained also by the addition of mAbs specific for NCR, thus implying that these tumors expressed the still undefined NCR ligands as well. On the other hand, AML did not express NKG2D ligands and their lysis was inhibited by mAbs to NCR but not to NKG2D [34]. Again, the inhibitory effect was not complete using only mAbs to NCR. Since AML expressed PVR and/or Nectin-2 (i.e. the DNAM-1 ligands) [60], it was conceivable that these receptor–ligand interactions could play a role complementary to NCR in the lysis of AML. This was indeed the case and complete inhibition of lysis was obtained by the simultaneous masking of NCR and DNAM-1 [34].
PVR also plays a central role in the lysis of neuroblastoma [61]. Neuroblastomas are HLA-class I-negative tumors that thus escape possible T cell-mediated responses. In addition, they lack conventional adhesion molecules thus rendering difficult their susceptibility to cell-mediated lysis. Neuroblas- toma cells that had been freshly isolated from BM generally displayed a modest susceptibility to NK-mediated lysis, as compared to neuroblastoma cell lines [61]. However, approx- imately 50% of the cases analyzed were partially lysed while the remaining were resistant. A remarkable phenotypic dif- ference between the two groups was the expression of PVR, restricted to those tumors susceptible to lysis. In these cases, however, the inhibition of lysis was achieved by the simulta- neous blocking of DNAM-1 and NCR. These results imply a cooperation between these receptors in inducing NK cell trig- gering. The finding that those neuroblastomas lacking PVR surface expression were resistant to lysis suggests that, at least in this tumor, PVR/DNAM-1 interaction is essential for obtaining responses via NCR. This could be related to a core- ceptor function of DNAM-1 or to the fact that, in the absence of the main adhesion interactions (e.g. LFA-1/ICAM-1), DNAM-1/PVR could serve primarily an adhesive function allowing NK activation and killing via NCR [5].
4. Concluding remarks
Although many central questions regarding NK cell recep- tors and their ligands have been answered, there are still relevant issues that need to be clarified in order to better understand the NK cell physiology and pathophysiology. One major problem is the identification of the cellular ligands for major triggering receptor, such as the NCR. Available information is compatible with the concept that, similar to MICA/B, PVR or Nectin-2, they may also be represented by molecules primarily expressed by cells that have been “stressed” by activating signals, temperature, tumor trans- formation or viral infection. In addition, novel molecular interactions should be explored. For example, a recently iden- tified surface molecule expressed by neuroblastomas (but also by other more common tumors, such as carcinomas and melanomas) “protects” this tumor from NK-mediated lysis [62]. This molecule, termed 4Ig-B7-H3, is a novel member of the B7 family [63]. The protective effect could be explained by the interaction with a still undefined inhibitory receptor expressed by NK cells. Additional molecules could have a similar functional capability and exert an inhibitory effect on NK cells, possibly upon interaction with one of the still orphan inhibitory receptors identified on NK cells [4].
It is evident that further identification of surface molecules involved in NK cell function (primarily of ligands for acti- vating receptors) as well as a better understanding of the molecular mechanisms governing not only NK cell activation or inactivation but also their migration to normal or compro- mised tissues would be of great help also in designing novel strategies for NK-based immunotherapy of cancer or severe viral infections (e.g. CMV in immunocompromized patients).
Acknowledgements
This work was supported by grants awarded by Asso- ciazione Italiana per la Ricerca sul Cancro (A.I.R.C.), Istituto Superiore di Sanita` (I.S.S.), Ministero della Salute- RF 2002/149, Ministero dell’Istruzione dell’Universita` e della Ricerca (M.I.U.R.), FIRB-MIUR progetto- cod.RBNE017B4C; Ministero dell’Universita` e della Ricerca Scientifica e Tecnologica (M.U.R.S.T.), Euro- pean Union FP6, LSHB-CT-2004-503319-Allostem, and Compagnia di San Paolo.
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[58] Castriconi R, Cantoni C, Della Chiesa M, Vitale M, Marcenaro E, Conte R, Biassoni R, Bottino C, Moretta L, Moretta A. Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Proc Natl Acad Sci USA 2003;100:4120–5.
[59] Pende D, Rivera P, Marcenaro S, Chang CC, Biassoni R, Conte R, Kubin M, Cosman D, Ferrone S, Moretta L, Moretta A. Major his- tocompatibility complex class I-related chain A and UL16-binding protein expression on tumor cell lines of different histotypes: anal- ysis of tumor susceptibility to NKG2D-dependent natural killer cell cytotoxicity. Cancer Res 2002;62:6178–86.
[60] Bottino C, Castriconi R, Pende D, Rivera P, Nanni M, Carnemolla B, Cantoni C, Grassi J, Marcenaro S, Reymond N, Vitale M, Moretta L, Lopez M, Moretta A. Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J Exp Med 2003;198:557–67.
[61] Castriconi R, Dondero A, Corrias MV, Lanino E, Pende D, Moretta L, Bottino C, Moretta A. Natural killer cell-mediated killing of freshly isolated neuroblastoma cells: critical role of DNAX accessory molecule-1-poliovirus receptor interaction. Cancer Res
2004;64:9180–4.
[62] Castriconi R, Dondero A, Augugliaro R, Cantoni C, Carnemolla B,
Sementa AR, Negri F, Conte R, Corrias MV, Moretta L, Moretta A, Bottino C. Identification of 4Ig-B7-H3 as a neuroblastoma-associated
moleculethatexertsaprotectiverolefromanNKcell-mediatedlysis.
Proc Natl Acad Sci USA 2004;101:12640–5.
[63] Moretta A, Bottino C. Commentary, Regulated equilibrium between
opposite signals: a general paradigm for T cell function? Eur J
Immunol 2004;34:2084–8.