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Keywords:

  • CD94;
  • Cytomegalovirus;
  • HLA-E;
  • Human;
  • Infection;
  • NK cells;
  • NKG2C

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Involvement of CD94/NKG2 lectin-like receptors in the NK-cell response to HCMV
  5. HCMV infection promotes the expansion of NKG2Cbright NK cells in healthy individuals
  6. Effect of HCMV infection on NK-cell subset distribution during early childhood
  7. Influence of the NKG2C genotype on the NK-cell response to HCMV
  8. Impact of HCMV infection on the NKR distribution in immunocompromised patients
  9. Is the NKG2C+ NK-cell expansion HCMV-specific?
  10. How does HCMV infection reshape the NK-cell compartment?
  11. Concluding remarks: Implications for clinical studies
  12. Acknowledgements
  13. Conflict of interest
  14. References

As discussed in this review, human cytomegalovirus (HCMV) infection in healthy individuals is associated with a variable and persistent increase of NK cells expressing the CD94/NKG2C activating receptor. The expansion of NKG2C+ NK cells reported in other infectious diseases is systematically associated with HCMV co-infection. The functionally mature NKG2Cbright NK-cell subset expanding in HCMV+ individuals displays inhibitory Ig-like receptors (KIR and LILRB1) specific for self HLA class I, and low levels of NKp46 and NKp30 activating receptors. Such reconfiguration of the NK-cell compartment appears particularly marked in immunocompromised patients and in children with symptomatic congenital infection, thus suggesting that its magnitude may be inversely related with the efficiency of the T-cell-mediated response. This effect of HCMV infection is reminiscent of the pattern of response of murine Ly49H+ NK cells against murine CMV (MCMV), and it has been hypothesized that a cognate interaction of the CD94/NKG2C receptor with HCMV-infected cells may drive the expansion of the corresponding NK-cell subset. Yet, the precise role of NKG2C+ cells in the control of HCMV infection, the molecular mechanisms underlying the NK-cell compartment redistribution, as well as its putative influence in the response to other pathogens and tumors remain open issues.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Involvement of CD94/NKG2 lectin-like receptors in the NK-cell response to HCMV
  5. HCMV infection promotes the expansion of NKG2Cbright NK cells in healthy individuals
  6. Effect of HCMV infection on NK-cell subset distribution during early childhood
  7. Influence of the NKG2C genotype on the NK-cell response to HCMV
  8. Impact of HCMV infection on the NKR distribution in immunocompromised patients
  9. Is the NKG2C+ NK-cell expansion HCMV-specific?
  10. How does HCMV infection reshape the NK-cell compartment?
  11. Concluding remarks: Implications for clinical studies
  12. Acknowledgements
  13. Conflict of interest
  14. References

The human NK-cell compartmentis phenotypically and functionally heterogeneous, containing populations at distinct maturation stages, as well as NK-cell subsets which display different NK-cell receptor (NKR) combinations with a clonal distribution pattern [1-3]. The diversity of the human NKR repertoire is genetically determined by the existence of a variety of killer-cell immunoglobulin-like receptor (KIR) haplotypes [4], and is believed to be modulated by cognate KIR-HLA class I (HLA-I) interactions during NK-cell maturation [5].

Similarly to T and B lymphocytes, NK cells may undergo clonal proliferation and late differentiation events, potentially skewing the NKR distribution. In this regard, human cytomegalovirus (HCMV) has been reported to induce in both healthy individuals and those with different pathological conditions a persistent reconfiguration of the NK-cell compartment, the hallmark of which is the expansion of an NK-cell subset displaying high surface levels of the CD94/NKG2C activating NKR specific for HLA-E [6]. Open questions concerning the mechanisms and putative clinical implications of the NK-cell homeostatic adaptation to this common viral infection are discussed in this review.

HCMV is a complex betaherpesvirus (230 kb, ∼170 ORF) capable of replicating in different cell types, which is commonly transmitted by secretions [7, 8]. HCMV infects all human populations with a variable prevalence (∼50–100%), depending on socioeconomic factors [9]. This viral infection generally follows a subclinical course in immunocompetent hosts and remains latent, undergoing occasional reactivation. Vertical transmission during pregnancy may cause congenital infection in ∼0.5–2% newborns, of whom ∼10% develop symptoms potentially associated with important sequelae (i.e. mental retardation and deafness) [10, 11]. Viral excretion in milk causes early postnatal infection, which may be symptomatic (e.g. neutropenia, thrombocytopenia, pneumonia), particularly in premature infants. HCMV infection/reactivation becomes an important cause of morbidity in immunodeficient (e.g. AIDS) and immunosuppressed patients (e.g. transplant recipients) [8, 12], and has been related with the development of atherosclerosis [13] and immunosenescence [14].

Host-pathogen evolutionary adaptation allows HCMV to establish a lifelong persistent infection, successfully disseminating with minimal pathogenic consequences at the population level. The success in reaching such a status quo resides with the ability of the virus to remain latent, and to escape from innate and adaptive immune mechanisms. From the host side, the combined action of NK and T cells, together with specific Ig production, contribute to control viral replication. HCMV encodes for a set of viral proteins (i.e. US2, US3, US6, US10, US11) that inhibit surface expression of HLA class I molecules (HLA-I) in infected cells [15, 16], thus interfering with antigen presentation to cytolytic CD8+ T cells. As a consequence, engagement of inhibitory NKRs specific for HLA-I molecules (i.e. KIR, CD94/NKG2A and LILRB1) is impaired, lowering the threshold for NK-cell activation against infected cells. NK-cell effector functions are triggered by NKRs specific for ligands that are constitutively expressed or induced upon infection, and HCMV has reciprocally developed a variety of immune evasion strategies [17-19].

Involvement of CD94/NKG2 lectin-like receptors in the NK-cell response to HCMV

  1. Top of page
  2. Abstract
  3. Introduction
  4. Involvement of CD94/NKG2 lectin-like receptors in the NK-cell response to HCMV
  5. HCMV infection promotes the expansion of NKG2Cbright NK cells in healthy individuals
  6. Effect of HCMV infection on NK-cell subset distribution during early childhood
  7. Influence of the NKG2C genotype on the NK-cell response to HCMV
  8. Impact of HCMV infection on the NKR distribution in immunocompromised patients
  9. Is the NKG2C+ NK-cell expansion HCMV-specific?
  10. How does HCMV infection reshape the NK-cell compartment?
  11. Concluding remarks: Implications for clinical studies
  12. Acknowledgements
  13. Conflict of interest
  14. References

The CD94 and NKG2 genes are clustered at the NK gene complex (NKC) on human chromosome 12 [20, 21], coding for lectin-like membrane glycoproteins which are assembled as heterodimers [22-24]. The CD94/NKG2A inhibitory receptor recruits the SHP-1 tyrosine phosphatase through the NKG2A “immunoreceptor tyrosine based inhibition motifs” (ITIMs), whereas CD94/NKG2C is associated with the ITAM-bearing DAP12 adapter, signaling via protein tyrosine kinase-dependent pathways [25]. Expression at the protein level of NKG2E, a third member of the gene family, which generates two transcripts (NKG2E and NKG2H) by alternative splicing, remains uncertain as flow cytometry data with specific mAbs are not available.

Both CD94/NKG2A and CD94/NKG2C specifically recognize HLA-E [26-28], which presents hydrophobic nonamers derived from the leader sequences of other HLA-I molecules, involving a TAP-dependent mechanism [29, 30]. This class Ib molecule exhibits a characteristic allelic dimorphism depending on the presence, at position 107, of an Arg (HLA-ER107) or a Gly (HLA-EG107) [31]. HLA-E-bound peptides determine a variable affinity for CD94/NKG2 NKR [32, 33], and resolution of the structure of a CD94/NKG2A-HLA-E complex revealed that CD94 dominates the interaction [34]. The inhibitory CD94/NKG2A NKR contributes to monitor normal HLA-I expression but the biological role of CD94/NKG2C, with a lower affinity for HLA-E, remains unclear. CD94/NKG2A plays a similar function in mice, recognizing Qa-1b bound to MHC class I leader peptides, whereas information on NKG2C expression and function is scarce [35, 36]. A key role for CD94 in immune defense against infection by murine poxvirus has been recently reported [37], suggesting the involvement of an activating CD94/NKG2 receptor.

HLA-E has been shown to bind other peptide sequences derived from Hsp60 and some pathogens, though their biological relevance is uncertain [31, 38-40]. The affinity of CD94/NKG2A for such HLA-E-peptide complexes is generally lower than that conferred by endogenous class I-derived nonamers, suggesting that their expression would promote the response of NKG2A+ NK cells [38]. On the other hand, there is no evidence that any of these complexes may trigger CD94/NKG2C signaling.

A special case is a peptide from the leader sequence of the UL40 molecule, well conserved in different HCMV strains and identical to that of some HLA-I alleles. Though the function of the UL40 protein is unknown, the UL40-derived peptide was reported to preserve HLA-E expression in HCMV-infected fibroblasts, protecting them against NKG2A+ NK cells, and implying that this complex should be resistant to viral proteins which down-regulate HLA-I [41-43]. Indeed, HLA-E expression appeared constitutively unaffected by US2 and US11 HCMV proteins [44]; moreover, when bound to the UL40 peptide it became also refractory to the action of US6, a TAP inhibitor which impairs endogenous peptide presentation [41]. On the other hand, Falk et al. [45] reported that downregulation of HLA-I molecules overrides the putative ability of this complex to prevent the NK-cell response against infected fibroblasts; differences in the experimental conditions may underlie this discrepancy. Recently, we observed that surface HLA-E was partially down-regulated in HCMV-infected moDCs which triggered autologous NKG2A+ NK-cell degranulation, thus indicating that the effectiveness of this putative immune evasion mechanism may vary in different cell types [46]. We hypothesize that the availability of the UL40 peptide might be insufficient for preserving the higher steady-state surface levels of the class Ib molecule in moDCs, as compared with fibroblasts. Of note, sequencing of peptides eluted from HLA-E in HCMV-infected cells has not been reported. This information would provide direct evidence for the presence of the HLA-E-bound UL40-derived nonamer in infected cells, eventually allowing the identification of other HLA-E-presented viral peptides. Expression of UL40 signal peptide by recombinant adenovirus has been shown to stabilize surface expression of the UL18 HCMV class I-like molecule in transfectants [47]. The biological significance of these observations in the context of HCMV infection is intriguing, and no unequivocal evidence proving that such complexes may functionally interact with CD94/NKG2 receptors has thus far been reported.

HCMV infection promotes the expansion of NKG2Cbright NK cells in healthy individuals

  1. Top of page
  2. Abstract
  3. Introduction
  4. Involvement of CD94/NKG2 lectin-like receptors in the NK-cell response to HCMV
  5. HCMV infection promotes the expansion of NKG2Cbright NK cells in healthy individuals
  6. Effect of HCMV infection on NK-cell subset distribution during early childhood
  7. Influence of the NKG2C genotype on the NK-cell response to HCMV
  8. Impact of HCMV infection on the NKR distribution in immunocompromised patients
  9. Is the NKG2C+ NK-cell expansion HCMV-specific?
  10. How does HCMV infection reshape the NK-cell compartment?
  11. Concluding remarks: Implications for clinical studies
  12. Acknowledgements
  13. Conflict of interest
  14. References

According to the distribution of CD94/NKG2 receptors, several NK-cell subsets can be found in peripheral blood (i.e. NKG2A+/C, NKG2A/C+, NKG2A+/C+, and NKG2A/C). In HCMV-seronegative individuals, NKG2A+/C and NKG2A/C NK cells are predominant and only minor proportions of the other subsets are detectable.

We originally described that increased proportions of NK cells bearing CD94/NKG2C were associated with HCMV seropositivity in healthy blood donors, being apparently unrelated to KIR haplotypes or to the HLA-E dimorphism [6]. As compared with NKG2A+ NK cells, NKG2C+ NK cells expressed lower surface levels of triggering NKp46 and NKp30 NCRs, and contained higher proportions of LILRB1+ and KIR+ cells. More recently, increased numbers of NKG2C+ cells were also detected in HCMV+ children indicating that the NK-cell compartment redistribution may occur early in life [48, 49]. The existence of two NKG2C+ NK-cell subsets differing in surface staining intensity of the receptor was noticed; only NKG2Cbright cells were considered in our first report, whereas total NKG2C+ cells have been counted in subsequent studies.

A recent systematic analysis in a cohort of young healthy adults has confirmed these findings, revealing additional phenotypic differences between both NKG2C+ cell subsets (our unpublished data). A fraction of NKG2Cdim cells co-express NKG2A, whereas NKG2Cbright NK cells are NKG2A and display lower surface levels of NKp46, NKp30 and CD161 NKR; both subsets comparably express CD16 and NKG2D activating NKR. Moreover, the expanded NKG2C+ populations from healthy HCMV+ blood donors predominantly display inhibitory KIR specific for self HLA-C1 or/and -C2 allotypes, suggesting that their cognate interaction modulates their differentiation/expansion driven by HCMV [50]. In this report, NKG2C NK-cell populations with an oligoclonal activating KIR expression pattern (i.e. KIR2DS2, 2DS4, 3DS1) were also detected in some HCMV+ blood donors.

The NKG2Cbright phenotype is exclusively found in a subgroup of HCMV+ individuals (∼50%), correlating with the expansion of NKG2C+ NK cells; in contrast, only smaller proportions of NKG2Cdim NK cells are found in other HCMV+ and all HCMV-seronegative individuals, including cord blood samples. The magnitude of the HCMV imprint on the NK-cell compartment is quite variable. In some HCMV+ subjects, NKG2Cbright NK cells represent >50% of the total NK-cell population, in sharp contrast with others who only display small proportions of NK cells with an NKG2Cdim phenotype. Of note, both NKG2C+ NK-cell subsets co-exist in samples from some HCMV+ individuals (our unpublished data). We hypothesize that these two NKG2C+ subsets represent distinct maturation stages, and that the NKG2Cbright population may derive from NKG2Cdim cells. NKG2A is detectable at early stages of NK-cell differentiation, whereas little information is currently available on the expression of NKG2C during NK-cell ontogeny. CD56dim NKG2A+ KIR+ NK cells have been proposed to differentiate into CD56dim NKG2A KIR+ cells [51, 52]. This view of human NK-cell maturation should be revised considering NKG2C expression and the influence of HCMV infection.

Altogether, these observations support that differentiation and expansion of the NKG2Cbright subset in response to HCMV infection is encompassed by more profound changes in NKR distribution. Remarkably, the HCMV imprint on the NKR repertoire is rather stable over time (our unpublished data and [6, 50]). The putative basis for individual differences in the steady state NKR redistribution associated with HCMV infection is further discussed in the next sections.

NKRs specific for HLA-I molecules (i.e. KIR, CD94/NKG2, and LILRB1) are also expressed by T lymphocytes with an effector-memory phenotype [53]. In particular, NKG2C is detectable in TcRαβ CD4+ and CD8+ as well as TCRγδ T-cell subsets [54]; moreover, engagement of the CD94/NKG2C receptor was shown to trigger T-cell-mediated cytotoxicity, cytokine production and proliferation [55]. Increased proportions of NKG2C+ T cells, different from CTLs specific for immunodominant HCMV antigens, were also detected in HCMV+ individuals [6]. The role in the anti-viral response of this minor subset of NKG2C+ CTLs, also found among intestinal intraepithelial lymphocytes [56], deserves attention.

Effect of HCMV infection on NK-cell subset distribution during early childhood

  1. Top of page
  2. Abstract
  3. Introduction
  4. Involvement of CD94/NKG2 lectin-like receptors in the NK-cell response to HCMV
  5. HCMV infection promotes the expansion of NKG2Cbright NK cells in healthy individuals
  6. Effect of HCMV infection on NK-cell subset distribution during early childhood
  7. Influence of the NKG2C genotype on the NK-cell response to HCMV
  8. Impact of HCMV infection on the NKR distribution in immunocompromised patients
  9. Is the NKG2C+ NK-cell expansion HCMV-specific?
  10. How does HCMV infection reshape the NK-cell compartment?
  11. Concluding remarks: Implications for clinical studies
  12. Acknowledgements
  13. Conflict of interest
  14. References

An inefficient immune response to viral infections in utero or early after birth is known to be associated with increased viral replication levels and a higher risk to follow a chronic course, attributable to the immaturity of the immune system that favors the establishment of partial T-cell tolerance [57]. HCMV infection in childhood promotes an expansion of NKG2Cbright NK cells [48] and, as shown recently, the effect appeared particularly marked in children who had suffered congenital symptomatic infection, remaining detectable years after birth [49]. The high proportions of LILRB1+ NK and T cells observed in these patients further illustrate the intensity of the challenge imposed by HCMV to the immune system. It is conceivable that priming of the NK-cell compartment during HCMV infection in infants may influence the subsequent development of innate and adaptive immune responses.

Unexpectedly, NKG2C+ NK-cell expansions were limited in children with asymptomatic congenital infection indicating that, regardless of the time of the first contact with the pathogen, additional variables (e.g. viral load, virus and host genetics) determine the magnitude of the HCMV imprint on the NK-cell compartment [49]. Such factors presumably account as well for the wide differences observed between healthy HCMV+ adults. We hypothesize that the group exhibiting greater expansions of NKG2Cbright cells might include some subjects infected in early childhood who maintain this phenotype lifelong.

Influence of the NKG2C genotype on the NK-cell response to HCMV

  1. Top of page
  2. Abstract
  3. Introduction
  4. Involvement of CD94/NKG2 lectin-like receptors in the NK-cell response to HCMV
  5. HCMV infection promotes the expansion of NKG2Cbright NK cells in healthy individuals
  6. Effect of HCMV infection on NK-cell subset distribution during early childhood
  7. Influence of the NKG2C genotype on the NK-cell response to HCMV
  8. Impact of HCMV infection on the NKR distribution in immunocompromised patients
  9. Is the NKG2C+ NK-cell expansion HCMV-specific?
  10. How does HCMV infection reshape the NK-cell compartment?
  11. Concluding remarks: Implications for clinical studies
  12. Acknowledgements
  13. Conflict of interest
  14. References

A homozygous deletion of the NKG2C gene was originally reported in ∼4% Dutch and Japanese healthy individuals [58], and similar results have been recently obtained in a Spanish cohort [59]. Whether this genotype has any implications in the response to HCMV is uncertain, and the frequency of the homozygous deletion was not increased in newborns with symptomatic congenital infection [49]. Nevertheless, recent studies revealed that HCMV+ NKG2C+/+ children and adults tend to display, under steady state conditions, greater numbers of NKG2Cbright cells as compared with those in hemizygous NKG2C+/del subjects. Remarkably, quantitative differences in NKG2C surface expression levels and in the functional response to receptor engagement were noticed comparing samples from NKG2C+/+ and NKG2C+/del subjects [49] (our unpublished data). These data support a correlation of NKG2C zygosity with the magnitude/persistence of the NK-cell redistribution in healthy HCMV+ donors, providing clues on the mechanism(s) whereby the NKG2C genotype may influence the proliferation/survival of NKG2C+ cells in response to HCMV infection, and indirectly supporting an active involvement of the receptor in this process.

A relationship of the NKG2C genotype with clinical course of HIV-1+ patients has been recently reported [60]. Though potentially of interest, this study is difficult to interpret as HCMV co-infection was disregarded, despite being previously associated with NKG2C+ NK-cell expansion in HIV-1+ patients, as discussed below.

Impact of HCMV infection on the NKR distribution in immunocompromised patients

  1. Top of page
  2. Abstract
  3. Introduction
  4. Involvement of CD94/NKG2 lectin-like receptors in the NK-cell response to HCMV
  5. HCMV infection promotes the expansion of NKG2Cbright NK cells in healthy individuals
  6. Effect of HCMV infection on NK-cell subset distribution during early childhood
  7. Influence of the NKG2C genotype on the NK-cell response to HCMV
  8. Impact of HCMV infection on the NKR distribution in immunocompromised patients
  9. Is the NKG2C+ NK-cell expansion HCMV-specific?
  10. How does HCMV infection reshape the NK-cell compartment?
  11. Concluding remarks: Implications for clinical studies
  12. Acknowledgements
  13. Conflict of interest
  14. References

Increased numbers of NKG2C+ NK cells have been observed following HCMV infection/reactivation in different clinical settings, further supporting a direct causal relationship. A patient with a severe T-cell immunodeficiency (i.e. IL-7R alpha chain mutation) exhibited a marked NKG2C+ lymphocytosis coinciding with acute HCMV infection [61]. Remarkably, this response was associated with a 3-log reduction of viremia, prior to the administration of anti-viral therapy. This case report suggests that NKG2C+ NK cells may, at least partially, contain the viral infection in the absence of T cells.

HCMV reactivation in immunosuppressed kidney transplant recipients was shown to promote an expansion of NKG2Cbright NK cell numbers, which remained elevated after a contraction phase [62]. These NK-cell populations display CD57, a marker related to late differentiation of NK and cytotoxic T cells. We have studied a cohort of kidney recipients, assessing the NK-cell phenotype in cryopreserved PBMC samples obtained at different times post-transplant. Greater numbers of NKG2C+ NK cells were detected in the group of transplant recipients as compared with controls, and the differences persisted in cases studied >10 years after renal transplantation (Yélamos and López-Botet, unpublished). The putative relationship of NKG2C+ NK-cell expansion with different clinical variables is being currently addressed.

A marked and sustained expansion of NKG2C+ NK-cell populations has been reported following HCMV reactivation in cord blood transplant (CBT) recipients, becoming the major circulating NK-cell subset over one year post-transplant [63, 64]. NKG2C+ cells were also found among the CD56 CD16+ NK-cell subset [63], whose phenotypic and functional features have been recently reviewed [65]. In contrast to NK-cell populations in non-infected CBT recipients, the expanding NKG2C+ NK cells expressed a dominant inhibitory KIR specific for self HLA-I and were functionally competent, thus supporting that the viral infection promoted their differentiation and maturation from hematopoietic progenitors [63, 64]. After allogeneic hematopoietic stem cell transplantation (HSCT) from HCMV+ donors, a sustained expansion of NKG2C+ cells was detected in HCMV+ recipients, even in the absence of overt viremia, but not in HCMV seronegative subjects [66]. The possibility that NKG2C+ cells might exert an anti-leukemic effect is envisaged and will be discussed in the last section.

Altogether, these observations in immunocompromised patients point out that the magnitude of the HCMV imprint on the NK-cell compartment appears inversely related to the T-cell-mediated control of the viral infection, and might represent a compensatory mechanism in anti-viral defense. The relationship between the expansion of NKG2C+ NK cells and the virus-specific T-cell response should be explored in healthy donors.

Is the NKG2C+ NK-cell expansion HCMV-specific?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Involvement of CD94/NKG2 lectin-like receptors in the NK-cell response to HCMV
  5. HCMV infection promotes the expansion of NKG2Cbright NK cells in healthy individuals
  6. Effect of HCMV infection on NK-cell subset distribution during early childhood
  7. Influence of the NKG2C genotype on the NK-cell response to HCMV
  8. Impact of HCMV infection on the NKR distribution in immunocompromised patients
  9. Is the NKG2C+ NK-cell expansion HCMV-specific?
  10. How does HCMV infection reshape the NK-cell compartment?
  11. Concluding remarks: Implications for clinical studies
  12. Acknowledgements
  13. Conflict of interest
  14. References

We originally reported that the serological status for other herpesviruses (i.e. EBV and HSV-1) was unrelated with the numbers of NKG2C+ cells [6]. Moreover, we proposed that HCMV co-infection accounts for increased proportions of NKG2C+ cells observed in HIV-1+ patients [67], a conclusion further supported by other reports in which this variable was considered [68, 69]. Recently, NKG2C+ NK-cell expansions have been reported in several acute and chronic viral infections (i.e. Hantavirus, Chikungunya, HCV and HBV), being systematically associated to HCMV co-infection [70-72], thus suggesting that the pre-existing HCMV-mediated redistribution of the NK-cell compartment is amplified. As shown in immunocompromised patients, it is likely that the inefficient T-cell-mediated control of HCMV in HIV-1+ cases may favor NKG2C+ NK-cell expansion, and a similar situation might occur in the course of other infections. Moreover, cytokine secretion during the anti-viral immune response might promote HCMV reactivation and boost the proliferation of bystander NKG2Cbright NK cells [73, 74]

From this standpoint, it becomes evident that HCMV co-infection becomes a potentially important confounding variable in clinical studies focussed on the cellular NKR distribution. Thus previous reports in infectious diseases in which HCMV co-infection was not considered should be revised.

How does HCMV infection reshape the NK-cell compartment?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Involvement of CD94/NKG2 lectin-like receptors in the NK-cell response to HCMV
  5. HCMV infection promotes the expansion of NKG2Cbright NK cells in healthy individuals
  6. Effect of HCMV infection on NK-cell subset distribution during early childhood
  7. Influence of the NKG2C genotype on the NK-cell response to HCMV
  8. Impact of HCMV infection on the NKR distribution in immunocompromised patients
  9. Is the NKG2C+ NK-cell expansion HCMV-specific?
  10. How does HCMV infection reshape the NK-cell compartment?
  11. Concluding remarks: Implications for clinical studies
  12. Acknowledgements
  13. Conflict of interest
  14. References

The cellular and molecular mechanisms whereby HCMV resets NK-cell compartment homeostasis are intriguing. The response of the NKG2C+ NK-cell population to HCMV is reminiscent of that shown by murine Ly49H+ NK cells, which specifically recognize the m157 viral glycoprotein in MCMV-infected cells [75-77]. After sequential expansion and contraction phases in response to the viral infection, Ly49H+ NK cells tend to persist in the circulation, conferring a more efficient defense against re-infection [78]. The term “memory NK cell” has been coined to define this pattern of response [79], and it has been speculated that NKG2Cbright NK cells might play a similar role in humans [80].

Based on the available information, we hypothesize that primary HCMV infection promotes the differentiation and proliferation of NKG2Cbright cells from a pool of progenitors, presumably included in the NKG2Cdim subset (Fig. 1). This effect tends to be amplified whenever an effective T-cell-mediated control of the infection is inefficient or delayed. Following the control of viremia, a fraction of differentiated NKG2Cbright NK cells survive after a contraction phase, generating a pool of long-lived NK cells with clonal expansion potential, variable at the single cell level depending on the number of cell divisions experienced. This process appears particularly sustained in NKG2C+/+ individuals and, similarly to the antigen-specific response of T lymphocytes, may be boosted by re-infection or reactivation, whenever the anti-viral T-cell-mediated response may fail to keep HCMV at bay. This contributes to explain the variable magnitude of the NKG2C+ NK-cell expansion in different subjects. Furthermore, the pool of NKG2Cbright cells is predictably heterogeneous under steady-state conditions, containing variable proportions of NKG2C+ “progenitors” proliferating in response to HCMV, together with terminally differentiated NK cells distinguishable by their expression of some surface markers (e.g. CD57) [81].

image

Figure 1. NK-cell compartment adaptation in response to HCMV. HCMV-seropositive individuals display a persistent expansion of a functionally mature NK-cell subset, whose hallmark is high surface expression of the activating receptor CD94/NKG2C (NKG2Cbright), together with the additional phenotypic differences noted, as compared with the NKG2C+ subset detected in HCMV-seronegative individuals (NKG2Cdim) and other HCMV+ subjects. Several factors, such as decreased T-cell mediated control, may underlie the variability in the magnitude of the steady state NK cell subset redistribution induced by HCMV. The potential implications of the HCMV imprint on the NK cell compartment on the immune response to other infections and tumours deserves further investigation.

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Based on the analogy with Ly49H+ NK cells, we hypothesized that recognition of virus-infected cells by CD94/NKG2C might specifically activate the corresponding NK-cell subset. Indeed, engagement of the receptor, either by a specific mAb or by HLA-E expressed in the 721.221 HLA-I defective cell line, specifically triggered not only NKG2C+ NK-cell effector functions but also their proliferation in response to IL-2 [55]. Furthermore, stimulation of PBMCs from HCMV+ donors with virus-infected fibroblasts promoted a late expansion of NKG2C+ NK cells [82], preceded by a wave of T-cell proliferation. Of note, this effect was only detected in samples from some HCMV+ donors displaying an expansion of NKG2C+ cells, but not in HCMV individuals, thus indicating that the experimental system did not fully reproduce the conditions driving the differentiation of NKG2Cbright NK cells during primary infection.

The NKG2C+ NK subset outgrowth was also observed when co-culturing purified NK cells with infected fibroblasts in the presence of IL-15, and was prevented by early treatment with a blocking F(ab´)2 anti CD94 mAb, further suggesting the involvement of the receptor. Infection with a panel of HCMV deletion mutants indicated that the viral molecules UL16, UL18 and UL40 were dispensable for NKG2C+ NK-cell expansion, which was abrogated when surface HLA-I expression was preserved in infected fibro-blasts [82].

Altogether these results suggest that a cognate interaction of CD94/NKG2C with a ligand in infected cells stimulates the proliferative response of the corresponding NK-cell subset, and this effect is overridden by the engagement of HLA-I-specific inhibitory receptors. Intriguingly, no experimental evidence supporting that CD94/NKG2C may specifically trigger NK-cell effector functions upon recognition of HCMV-infected cells has been obtained [46] (Gumá and López-Botet, unpublished results). Thus, further studies are warranted to precisely unravel the mechanisms whereby HCMV infection resets the NK-cell compartment homeostasis.

Concluding remarks: Implications for clinical studies

  1. Top of page
  2. Abstract
  3. Introduction
  4. Involvement of CD94/NKG2 lectin-like receptors in the NK-cell response to HCMV
  5. HCMV infection promotes the expansion of NKG2Cbright NK cells in healthy individuals
  6. Effect of HCMV infection on NK-cell subset distribution during early childhood
  7. Influence of the NKG2C genotype on the NK-cell response to HCMV
  8. Impact of HCMV infection on the NKR distribution in immunocompromised patients
  9. Is the NKG2C+ NK-cell expansion HCMV-specific?
  10. How does HCMV infection reshape the NK-cell compartment?
  11. Concluding remarks: Implications for clinical studies
  12. Acknowledgements
  13. Conflict of interest
  14. References

The available information points out that HCMV infection promotes a persistent reconfiguration of the NK-cell compartment, albeit of variable magnitude in different individuals. This effect appears inversely related to the effectiveness of T-cell-mediated control of the pathogen, presumably representing a compensatory defense mechanism. Despite the similarities with the specific response of Ly49H NK cells to MCMV, the molecular and cellular mechanisms underlying the expansion of NKG2C+ cells, and its precise role in the control of HCMV infection /reactivation remain open.

Beyond these basic questions, several considerations deserve attention from a practical standpoint for the development of clinical studies. Firstly, as stressed above, HCMV infection should be considered a relevant confounding variable in any clinical study assessing the NKR distribution, particularly in the context of other infections. Secondly, the variability of the imprint exerted by HCMV on the NK-cell compartment reveals qualitative differences of the individual host-pathogen relationship, not perceived through the conventional serological and cellular assays used to assess the adaptive immune response to HCMV. Thus, analyzing the NK-cell immunophenotype may provide novel insights on the participation of the virus in the pathogenesis of different clinical disorders. In this regard, a study on the NKR distribution was conducted considering the putative role of HCMV as a risk factor in the development of atherosclerosis and cardiovascular disease [13]. Our results revealed an association of these processes with chronic stimulation of the NK and T-cell compartments, but no relationship with the expansion of NKG2C+ cells was perceived. Considering the role attributed to HCMV in immunosenescence [14], an assessment of the NK-cell compartment reconfiguration is warranted in this context.

Thirdly, NKG2C+ NK-cell populations expanding by HCMV infection in HSCT recipients might exert an anti-leukemic effect. In this regard, early HCMV reactivation following allogeneic HSCT has been associated to a reduced risk of relapse in Acute Myeloid Leukemia (AML) patients [83]. In a different scenario, an NK/T-cell lymphocytosis following HCMV reactivation was also related to remission in cases of Chronic Myeloid Leukemia (CML) treated with Dasatinib, a kinase inhibitor used in case of resistance to Imatinib [84]. Despite the lack of precise data on the NK-cell phenotype in these clinical studies, an involvement of NKG2C+ NK-cells in the putative anti-leukemic effect is plausible. This hypothesis deserves special attention in the context of the development of immunotherapy protocols for hematological malignancies, commonly aimed to promote NK-cell mediated alloreactivity in HSCT, either harnessing the mismatch between donor KIR and recipient HLA-I or blocking their interaction with anti KIR mAbs [85-87]. Hypothetically, the restricted expression of self-reactive inhibitory KIR by the expanded mature donor NKG2Cbright NK-cell populations might favor the establishment of a potent and long-lasting alloreactive response against malignant cells.

Finally, it is conceivable that NK-cell-mediated innate immunity triggered by a given infectious agent may indirectly affect the defense against other pathogens. Interestingly, latent herpes virus infections have been reported to confer protection against bacterial infections [88, 89]. Thus, attention should be paid to the possibility that the marked and persistent changes of NKR distribution induced by HCMV in some individuals might condition, positively or negatively, the NK-cell response to other infections and tumors, eventually influencing as well the development of adaptive immunity as reported in mice [90].

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Involvement of CD94/NKG2 lectin-like receptors in the NK-cell response to HCMV
  5. HCMV infection promotes the expansion of NKG2Cbright NK cells in healthy individuals
  6. Effect of HCMV infection on NK-cell subset distribution during early childhood
  7. Influence of the NKG2C genotype on the NK-cell response to HCMV
  8. Impact of HCMV infection on the NKR distribution in immunocompromised patients
  9. Is the NKG2C+ NK-cell expansion HCMV-specific?
  10. How does HCMV infection reshape the NK-cell compartment?
  11. Concluding remarks: Implications for clinical studies
  12. Acknowledgements
  13. Conflict of interest
  14. References

This work was supported by grants from Plan Nacional de I+D (SAF2010-22153-C03), EU SUDOE program (SOE2/P1/E341) and Fundació La Marató de TV3 (121531) to ML-B and CV. AM is supported by Asociación Española Contra el Cáncer (AECC). We express our special gratitude to all past members of the team and external collaborators who contributed to build up the conceptual framework of this work.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Involvement of CD94/NKG2 lectin-like receptors in the NK-cell response to HCMV
  5. HCMV infection promotes the expansion of NKG2Cbright NK cells in healthy individuals
  6. Effect of HCMV infection on NK-cell subset distribution during early childhood
  7. Influence of the NKG2C genotype on the NK-cell response to HCMV
  8. Impact of HCMV infection on the NKR distribution in immunocompromised patients
  9. Is the NKG2C+ NK-cell expansion HCMV-specific?
  10. How does HCMV infection reshape the NK-cell compartment?
  11. Concluding remarks: Implications for clinical studies
  12. Acknowledgements
  13. Conflict of interest
  14. References
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