Adaptive NK cell response to human cytomegalovirus: Facts and open issues.

Human cytomegalovirus (HCMV) infection exerts broad effects on the immune system. These include the differentiation and persistent expansion of a mature NK cell subset which displays a characteristic phenotypic and functional profile hallmarked by expression of the HLA-E-specific CD94/NKG2C activating receptor. Based on our experience and recent advances in the field, we overview the adaptive features of the NKG2C+ NK cell response, discussing observations and open questions on: (a) the mechanisms and influence of viral and host factors; (b) the existence of other NKG2C- NK cell subsets sharing adaptive features; (c) the development and role of adaptive NKG2C+ NK cells in the response to HCMV in hematopoietic and solid organ transplant patients; (d) their relation with other viral infections, mainly HIV-1; and (e) current perspectives for their use in adoptive immunotherapy of cancer.

Microvascular inflammation in the absence of human leukocyte antigen-donor-specific antibody and C4d: An orphan category in Banff classification with cytotoxic T and natural killer cell infiltration.

Isolated microvascular inflammation (iMVI) without HLA donor-specific antibodies or C4d deposition in peritubular capillaries remains an enigmatic phenotype that cannot be categorized as antibody-mediated rejection (ABMR) in recent Banff classifications. We included 221 kidney transplant recipients with biopsies with ABMR (n = 73), iMVI (n = 32), and normal (n = 116) diagnoses. We compared peripheral blood leukocyte distribution by flow cytometry and inflammatory infiltrates in kidney transplant biopsies among groups. Flow cytometry showed fewer lymphocytes and total, CD4+, and CD8+ peripheral T cells in iMVI compared with ABMR and normal cases. ABMR and iMVI had fewer total natural Killer (NK) cells but more NKG2A+ NK cells. Immunohistochemistry indicated that ABMR and iMVI had greater CD3+ and CD68+ glomerular infiltration than normal biopsies, whereas CD8+ and TIA1+ cells showed only increased iMVI, suggesting they are cytotoxic T cells. Peritubular capillaries displayed more CD3+, CD56+, TIA1+, and CD68+ cells in both ABMR and iMVI. In contrast, iMVI had less plasma cell infiltration in peritubular capillaries and interstitial aggregates than ABMR. iMVI displayed decreased circulating T and NK cells mirrored by T cell and NK cell infiltration in the renal allograft, similar to ABMR. However, the lesser plasma cell infiltration in iMVI may suggest an antibody-independent underlying stimulus.

NK cells eliminate Epstein-Barr virus bound to B cells through a specific antibody-mediated uptake.

Epstein Barr virus (EBV) causes a highly prevalent and lifelong infection contributing to the development of some malignancies. In addition to the key role played by T cells in controlling this pathogen, NK cells mediate cytotoxicity and IFNγ production in response to EBV-infected B cells in lytic cycle, both directly and through antibody (Ab)-dependent activation. We recently described that EBV-specific Ab-dependent NK cell interaction with viral particles (VP) bound to B cells triggered degranulation and TNFα secretion but not B cell lysis nor IFNγ production. In this report we show that NK cell activation under these conditions reduced B cell transformation by EBV. NK cells eliminated VP from the surface of B cells through a specific and active process which required tyrosine kinase activation, actin polymerization and Ca2+, being independent of proteolysis and perforin. VP were displayed at the NK cell surface before being internalized and partially shuttled to early endosomes and lysosomes. VP transfer was encompassed by a trogocytosis process including the EBV receptor CD21, together with CD19 and CD20. Our study reveals a novel facet of the antibody-dependent NK cell mediated response to this viral infection.

Long-Term Evolution of the Adaptive NKG2C+ NK Cell Response to Cytomegalovirus Infection in Kidney Transplantation: An Insight on the Diversity of Host-Pathogen Interaction.

Human CMV infection is frequent in kidney transplant recipients (KTR). Pretransplant Ag-specific T cells and adaptive NKG2C+ NK cells associate with reduced incidence of infection in CMV+ KTR. Expansions of adaptive NKG2C+ NK cells were reported in posttransplant CMV-infected KTR. To further explore this issue, NKG2C+ NK, CD8+, and TcRγδ T cells were analyzed pretransplant and at different time points posttransplant for ≥24 mo in a cohort of CMV+ KTR (n = 112), stratified according to CMV viremia detection. In cryopreserved samples from a subgroup (n = 49), adaptive NKG2C+ NK cell markers and T cell subsets were compared after a longer follow-up (median, 56 mo), assessing the frequencies of CMV-specific T cells and viremia at the last time point. Increased proportions of NKG2C+ NK, CD8+, and TcRγδ T cells were detected along posttransplant evolution in viremia(+) KTR. However, the individual magnitude and kinetics of the NKG2C+ NK response was variable and only exceptionally detected among viremia(-) KTR, presumably reflecting subclinical viral replication events. NKG2C+ expansions were independent of KLRC2 zygosity and associated with higher viral loads at diagnosis; no relation with other clinical parameters was perceived. Increased proportions of adaptive NKG2C+ NK cells (CD57+, ILT2+, FcεRIγ-) were observed after resolution of viremia long-term posttransplant, coinciding with increased CD8+ and Vδ2- γδ T cells; at that stage CMV-specific T cells were comparable to viremia(-) cases. These data suggest that adaptive NKG2C+ NK cells participate with T cells to restore CMV replication control, although their relative contribution cannot be discerned.

Pretransplant adaptive NKG2C+ NK cells protect against cytomegalovirus infection in kidney transplant recipients.

Cytomegalovirus (CMV) infection constitutes a complication for kidney transplant recipients (KTR) and CMV-specific T cells reduce the risk of viral replication in seropositive patients. CMV promotes the adaptive differentiation and expansion of an NK cell subset, hallmarked by expression of the CD94/NKG2C receptor with additional characteristic features. We previously reported an association of pretransplant NKG2C+ NK cells with a reduced incidence of CMV infection. We have strengthened the analysis in cryopreserved peripheral blood mononuclear cells from an enlarged KTR cohort (n = 145) with homogeneous immunosuppression, excluding cases at low risk of infection (ie, CMV D-R-) or receiving antiviral prophylaxis. Moreover, adaptive NKG2C+ NK cell-associated markers (ie, NKG2A, CD57, Immunoglobulin-like transcript 2 [LIR1 or LILRB1], FcεRI γ chain, and Prolymphocytic Leukemia Zinc Finger transcription factor) as well as T lymphocyte subsets were assessed by multicolor flow cytometry. The relation of NKG2C+ NK cells with T cells specific for CMV antigens was analyzed in pretransplant patients (n = 29) and healthy controls (n = 28). Multivariate Cox regression and Kaplan-Meier analyses supported that NKG2C+ NK cells bearing adaptive markers were specifically associated with a reduced incidence of posttransplant symptomatic CMV infection; no correlation between NKG2C+ NK cells and CMV-specific T cells was observed. These results support that adaptive NKG2C+ NK cells contribute to control CMV infection in KTR.

Impact of cytomegalovirus infection on B cell differentiation and cytokine production in multiple sclerosis.

BACKGROUND: Human cytomegalovirus (HCMV) infection has been recently associated with a low risk of multiple sclerosis (MS), yet the basis behind this observation remains uncertain. In this study, we aimed to determine in MS patients whether HCMV induces modifications in the peripheral B cell compartment. METHODS: HCMV serostatus was determined in 73 MS patients (55 relapsing-remitting MS (RRMS); 18 progressive MS (PMS)) and 30 healthy controls, assessing their B cell immunophenotype and cytokine production (GM-CSF, IL-6, IL-10, and TNFα) by flow cytometry. RESULTS: HCMV seropositivity in untreated MS patients (n = 45) was associated with reduced switched memory B cells, contrasting with an opposite effect in PMS. Expansions of transitional B cells were observed in HCMV(+) IFNß-treated RRMS patients but not in HCMV(-) cases (p < 0.01), suggesting that HCMV may influence the distribution of B cell subsets modulating the effects of IFNß. Considering the B cell functional profile, HCMV(-) PMS displayed an increased secretion of proinflammatory cytokines (IL-6, TNFα) as compared to HCMV(+) PMS and RRMS cases (p < 0.001). CONCLUSIONS: Our study reveals an influence of HCMV infection on the phenotype and function of B cells, promoting early differentiation stages in RRMS and reducing the proinflammatory cytokine profile in advanced MS forms, which might be related with the putative protective role of this virus in MS.

Adaptive NKG2C+ natural killer cells are related to exacerbations and nutritional abnormalities in COPD patients.

Chronic obstructive pulmonary disease (COPD) is a chronic and often progressive disorder with a heterogeneous presentation and frequent systemic manifestations. Several aspects like persistence in smoking habit, continuous exacerbations, alpha-1-antitrypsin deficiency and inflammatory-immune response, are involved in the pathophysiology and progression of the disease. However, the role of natural killer (NK) cells remains controversial. Otherwise, human cytomegalovirus (HCMV) infection has been reported to induce an adaptive differentiation and expansion of an NK cell subset which carries the CD94/NKG2C receptor, which may contribute to an upset immune defense. For these reasons, our objective is to assess the distribution of NK cells and their subset in COPD patients and some of its phenotypes. METHODS: Peripheral blood samples were obtained from 66 COPD patients. HCMV serology and the proportions of total NK cells and the NKG2C+ and NKG2A+ subsets were evaluated by flow cytometry. The NKG2C genotype was also assessed. RESULTS: Eighty-eight per cent of COPD patients were HCMV(+), and the proportions of total NK cells were higher in patients with severe-very severe airway obstruction than in those with only mild-moderate involvement. There were no differences in the proportions of NKG2C+ cells between controls and COPD, either among COPD patients classified by severity of the disease. However, the percentage of NKG2C+ cells were higher in COPD patients with frequent exacerbations than in occasional exacerbators, and higher in cases with reduced lean mass (Fat free mass index) than in those with normal nutritional status. CONCLUSION: These results suggest a relationship between levels of NKG2C+ cells in COPD patients and clinical variables closely linked to a poor/worse prognosis.

Antibody-Dependent NK Cell Activation Differentially Targets EBV-Infected Cells in Lytic Cycle and Bystander B Lymphocytes Bound to Viral Antigen-Containing Particles.

NK cells have been reported to respond against EBV-infected B cells in the lytic cycle and to control the viral infection involving IFN-γ secretion. Early reports proposed a role for NK cell Ab-dependent cellular cytotoxicity (ADCC) triggered via FcγR-IIIA (CD16) in the response to EBV. In the current study, we revisited this issue, showing that serum from EBV+ individuals triggered vigorous NK cell degranulation and cytokine production (i.e., TNF-α and IFN-γ) against EBV-infected cells, enhancing NK cell activation. The effect was preferentially directed against cells in the lytic phase and was associated with surface expression of the gp350/220 envelope Ag. In contrast, binding of gp350+ particles, released by EBV-infected cells, to B cell lines or autologous primary B lymphocytes also promoted specific Ab-dependent NK cell degranulation and TNF-α production but induced minimal IFN-γ secretion. In that case, target cell damage appeared marginal compared with the effect of a control anti-CD20 Ab (rituximab) at concentrations that triggered similar NK cell activation, indicating that cell-associated gp350+ particles may divert the cytolytic machinery, impairing its direct action on the plasma membrane. These observations support that Ab-dependent NK cell activation plays an important role in the control of EBV, enhancing NK cell effector functions against infected B cells in the lytic cycle. In contrast, the data reveal that gp350+ particles bound to bystander B cells trigger Ab-dependent NK cell degranulation and TNF-α but not cytotoxicity or IFN-γ production, potentially favoring the progression of viral infection.

Adaptive NKG2C+ NK Cell Response and the Risk of Cytomegalovirus Infection in Kidney Transplant Recipients.

CMV infection in kidney transplant recipients (KTRs) has been associated with an increased risk for graft loss and reduced host survival. CMV promotes persistent expansions of NK cells expressing the CD94/NKG2C receptor. The NKG2C (KLRC2) gene is frequently deleted, and copy number influences the adaptive response of NKG2C+ NK cells. The distribution of NKG2C+ NK cells and NKG2C genotypes (NKG2C+/+, NKG2C+/del, NKG2Cdel/del) were studied in cross-sectional (n = 253) and prospective (n = 122) KTR cohorts. Assessment of CMV viremia was restricted to symptomatic cases in the retrospective study, but was regularly monitored in the prospective cohort. Overall, the proportions of NKG2C+ NK cells were significantly higher in KTRs who had suffered posttransplant symptomatic CMV infection in the cross-sectional study. Yet, along the prospective follow-up (3, 6, 12, and 24 mo), posttransplant NKG2C+ NK cell expansions were not observed in every patient with detectable viremia who received preemptive antiviral therapy, suggesting that the adaptive NK cell response may be inversely related with the degree of CMV control. Remarkably, the incidence of posttransplant viremia was reduced among cases with high pretransplant levels of NKG2C+ NK cells. The NKG2C genotype distribution was comparable in KTR and healthy controls, and greater proportions of NKG2C+ cells were detected in NKG2C+/+ than in NKG2C+/del patients. Yet, a trend toward increased NKG2C+/del and reduced NKG2C+/+ frequencies associated with symptomatic infection was appreciated in both cohorts. Altogether, our results indirectly support that adaptive NKG2C+ NK cells are involved in the control of CMV in KTRs.

Relationship of NKG2C Copy Number with the Distribution of Distinct Cytomegalovirus-Induced Adaptive NK Cell Subsets.

CD94/NKG2C and lack of FcεRγ (FcRγ) expression are considered markers of the adaptive NK cell response to human CMV (HCMV) infection. Despite the fact that FcRγ(-) and NKG2C(bright) NK cells share some phenotypic, epigenetic, and functional features, their relationship remains unclear. To address this issue, a systematic analysis of NKG2C(bright) and FcRγ expression was carried out in NK cells from a cohort of healthy young adults (n = 81) considering NKG2C copy number, previously related to the magnitude of NKG2C(+) NK cell expansion. NKG2C(bright) and FcRγ(-) NK cells coincided in a subgroup of HCMV(+) individuals, pointing to a common host-virus interaction pattern. Even though FcRγ loss was often confined to expanded NKG2C(bright) NK cells, both markers appeared occasionally dissociated, consistent with the existence of distinct adaptive NK cell subsets. Remarkably, FcRγ loss was mostly accumulated within the NKG2C(bright) subset in NKG2C(+/+) subjects, whereas NKG2C(-)FcRγ(-) NK cell subpopulations were more frequently detected in NKG2C(+/del) donors and also in NKG2C(del) (/del) individuals, independently of activating killer Ig-like receptor expression. The distribution of other NK receptors (i.e., killer Ig-like receptor, LILRB1, or CD57) supported a sequential differentiation from NKG2C(bright)FcRγ(+) to NKG2C(bright)FcRγ(-) NK cells. Noticeably, NKG2C(bright) NK cells produced more TNF-α in response to Ab-dependent activation, regardless of their FcRγ levels. Moreover, the TNF-α response of NKG2C(-)FcRγ(-) subpopulations was lower than that of concurrent NKG2C(bright)FcRγ(-) NK cells, further supporting that FcRγ levels and enhanced potential for cytokine production are uncoupled. Overall, our data extend the characterization of adaptive NK cell subsets that differentiate in response to HCMV, supporting a relationship between their distribution and NKG2C copy number.

The CD94/NKG2C+ NK-cell subset on the edge of innate and adaptive immunity to human cytomegalovirus infection.

Human cytomegalovirus (HCMV) causes a highly prevalent and lifelong infection, with a multifaceted impact in human health. NK cells play an important role in the immune response to HCMV and the virus has reciprocally developed a variety of immune evasion strategies. We originally reported that HCMV infection promotes, to a variable degree in healthy individuals, a redistribution of the NK-cell receptor (NKR) repertoire which persists under steady-state conditions. Its hallmark is an expansion of a mature NK-cell subset displaying high surface levels of the CD94/NKG2C activating receptor, with additional distinctive phenotypic and functional features. Such adaptation of host NK cells to HCMV infection, confirmed in different clinical settings, is particularly magnified in immunocompromised patients and influenced by NKG2C gene copy number. The mechanism(s) underlying the differentiation and proliferation of NKG2C+ NK cells, the basis for the individual differences in the magnitude of their expansion, and their precise role in anti-viral defence remain open issues. Moreover, the possibility that the impact of HCMV infection on the NK-cell compartment may exert a broader influence on immunity deserves further attention.

Impact of Zygosity on Bimodal Phenotype Distributions.

Allele number, or zygosity, is a clear determinant of gene expression in diploid cells. However, the relationship between the number of copies of a gene and its expression can be hard to anticipate, especially when the gene in question is embedded in a regulatory circuit that contains feedback. Here, we study this question making use of the natural genetic variability of human populations, which allows us to compare the expression profiles of a receptor protein in natural killer cells among donors infected with human cytomegalovirus with one or two copies of the allele. Crucially, the distribution of gene expression in many of the donors is bimodal, which indicates the presence of a positive feedback loop somewhere in the regulatory environment of the gene. Three separate gene-circuit models differing in the location of the positive feedback loop with respect to the gene can all reproduce the homozygous data. However, when the resulting fitted models are applied to the hemizygous donors, one model (the one with the positive feedback located at the level of gene transcription) is superior in describing the experimentally observed gene-expression profile. In that way, our work shows that zygosity can help us relate the structure and function of gene regulatory networks.

Interaction of the LILRB1 inhibitory receptor with HLA class Ia dimers.

Leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1) has been reported to interact with a wide spectrum of HLA class I (HLA-I) molecules, albeit with different affinities determined by allelic polymorphisms and conformational features. HLA-G dimerization and the presence of intracellular Cys residues in HLA-B7 have been shown to be critical for their recognition by LILRB1. We hypothesized that dimerization of classical HLA class Ia molecules, previously detected in exosomes, might enhance their interaction with LILRB1. A soluble LILRB1-Fc fusion protein and a sensitive cellular reporter system expressing a LILRB1-ζ chimera were employed to assess receptor interaction with different HLA class Ia molecules transfected in the human lymphoblastoid 721.221 cell line. Under these conditions, intracellular Cys residues and HLA-I dimerization appeared associated with increased LILRB1 recognition. On the other hand, a marginal interaction of LILRB1 with primary monocytic cells, irrespective of their high HLA-I expression, was enhanced by type I interferon (IFN). This effect appeared disproportionate to the cytokine-induced increase of surface HLA-I expression and was accompanied by detection of HLA class Ia dimers. Altogether, the results support that a regulated assembly of these noncanonical HLA-I conformers during the immune response may enhance the avidity of their interaction with LILRB1.

Antibody-mediated response of NKG2Cbright NK cells against human cytomegalovirus.

Human CMV (HCMV) infection promotes a variable and persistent expansion of functionally mature NKG2C(bright) NK cells. We analyzed NKG2C(bright) NK cell responses triggered by Abs from HCMV(+) sera against HCMV-infected MRC5 fibroblasts. Specific Abs promoted the degranulation (i.e., CD107a expression) and the production of cytokines (TNF-α and IFN-γ) by a significant fraction of NK cells, exceeding the low natural cytotoxicity against HCMV-infected targets. NK cell-mediated Ab-dependent cell-mediated cytotoxicity was limited by viral Ag availability and HLA class I expression on infected cells early postinfection and increased at late stages, overcoming viral immunoevasion strategies. Moreover, the presence of specific IgG triggered the activation of NK cells against Ab-opsonized cell-free HCMV virions. As compared with NKG2A(+) NK cells, a significant proportion of NKG2C(bright) NK cells was FcεR γ-chain defective and highly responsive to Ab-driven activation, being particularly efficient in the production of antiviral cytokines, mainly TNF-α. Remarkably, the expansion of NKG2C(bright) NK cells in HCMV(+) subjects was related to the overall magnitude of TNF-α and IFN-γ cytokine secretion upon Ab-dependent and -independent activation. We show the power and sensitivity of the anti-HCMV response resulting from the cooperation between specific Abs and the NKG2C(bright) NK-cell subset. Furthermore, we disclose the proinflammatory potential of NKG2C(bright) NK cells, a variable that could influence the individual responses to other pathogens and tumors.

NK Cell and Ig Interplay in Defense against Herpes Simplex Virus Type 1: Epistatic Interaction of CD16A and IgG1 Allotypes of Variable Affinities Modulates Antibody-Dependent Cellular Cytotoxicity and Susceptibility to Clinical Reactivation.

HSV-1 latently infects most humans, causing a variable clinical picture that depends, in part, on host genetic factors. Both IgG and its cellular FcRs, CD16A and CD32A-C (encoded by FCGR3A and FCGR2A-C, respectively, on chromosome 1), display polymorphisms that could affect their defensive function. Of potential relevance are a FCGR3A dimorphism resulting in CD16A-valine/phenylalanine-158 allotypes with different IgG affinity, variations conditioning NK cell expression of CD32B or CD32C, and IgG1 H chain (IGHG1) and kappa-chain (IGKC) polymorphisms determining allotypes designated G1m and Km. In this study, we assessed the contribution of Ig genetic variations and their interaction with FcR polymorphism to HSV-1 susceptibility, as well as their impact on NK cell-mediated Ab-dependent cellular cytotoxicity (ADCC). Our results show an epistatic interaction between IGHG1 and FCGR3A such that the higher affinity CD16A-158V/V genotype associates with an asymptomatic course of HSV-1 infection only in homozygotes for G1m3. Furthermore, CD16A-158V and G1m3 allotypes enhanced ADCC against opsonized HSV-1-infected fibroblasts. Conversely, Km allotypes and CD32B or CD32C expression on NK cells did not significantly influence HSV-1 susceptibility or ADCC. NK cells degranulating against immune serum-opsonized HSV-1-infected fibroblasts had heterogeneous phenotypes. Yet, enhanced ADCC was observed among NK cells showing a differentiated, memory-like phenotype (NKG2C(bright)NKG2A(-)CD57(+)FcRγ(-)), which expand in response to human CMV. These results extend our knowledge on the importance of immunogenetic polymorphisms and NK cell-Ab interplay in the host response against HSV-1 and point to the relevance of interactions between immune responses elicited during chronic coinfection by multiple herpesviruses.

Analysis of memory-like natural killer cells in human cytomegalovirus-infected children undergoing αß+T and B cell-depleted hematopoietic stem cell transplantation for hematological malignancies.

We analyzed the impact of human cytomegalovirus infection on the development of natural killer cells in 27 pediatric patients affected by hematological malignancies, who had received a HLA-haploidentical hematopoietic stem cell transplantation, depleted of both α/ß+ T cells and B cells. In line with previous studies in adult recipients of umbilical cord blood transplantation, we found that human cytomegalovirus reactivation accelerated the emergence of mature natural killer cells. Thus, most children displayed a progressive expansion of a memory-like natural killer cell subset expressing NKG2C, a putative receptor for human cytomegalovirus, and CD57, a marker of terminal natural killer cell differentiation. NKG2C(+)CD57(+) natural killer cells were detectable by month 3 following hematopoietic stem cell transplantation and expanded until at least month 12. These cells were characterized by high killer Ig-like receptors (KIRs) and leukocyte inhibitory receptor 1 (LIR-1) and low Siglec-7, NKG2A and Interleukin-18Rα expression, killed tumor targets and responded to cells expressing HLA-E (a NKG2C ligand). In addition, they were poor Interferon-γ producers in response to Interleukin-12 and Interleukin-18. The impaired response to these cytokines, together with their highly differentiated profile, may reflect their skewing toward an adaptive condition specialized in controlling human cytomegalovirus. In conclusion, in pediatric patients receiving a type of allograft different from umbilical cord blood transplantation, human cytomegalovirus also induced memory-like natural killer cells, possibly contributing to controlling infections and reinforcing anti-leukemia effects.

Adaptive natural killer cell response to cytomegalovirus and disability progression in multiple sclerosis.

BACKGROUND: Human cytomegalovirus (HCMV) causes a highly prevalent infection which may have a multifaceted impact on chronic inflammatory disorders. However, its potential influence in multiple sclerosis (MS) remains controversial. The HCMV-host interaction may induce an adaptive reconfiguration of the natural killer (NK) cell compartment, whose hallmark is a persistent expansion of peripheral NKG2C+ NK-cells. OBJECTIVE: The purpose of this study was to evaluate whether the HCMV-driven NKG2C+ NK-cell expansion is related to the MS clinical course. METHODS: Multicentre analysis of NKG2C expression and genotype according to HCMV serostatus and time of assignment of irreversible disability scores in 246 MS patients prospectively followed up in our institutions. RESULTS: NKG2C expression was unrelated to disease-modifying drugs, remained stable under steady-state conditions, and was higher in HCMV(+) NKG2C(+/+) homozygous individuals. NKG2C+ NK-cell expansion in HCMV(+) patients, as compared to HCMV(+) or HCMV(-) patients with lower NKG2C+ NK-cells proportions, conferred a lower risk of progression in Cox regression analysis (Expanded Disability Status Scale (EDSS)>3.0, hazard ratio (HR)=0.33, 95% confidence interval (CI) 0.15-0.71, p=0.005; EDSS>5.5, HR=0.23, 95% CI 0.07-0.74, p=0.014). Neither HCMV serostatus nor NKG2C genotype appeared to be related to disability progression. CONCLUSIONS: HCMV may exert a beneficial influence on MS, decreasing the risk of disability progression in those patients displaying a virus-driven NKG2C+ NK-cell expansion.

Adaptive reconfiguration of the human NK-cell compartment in response to cytomegalovirus: a different perspective of the host-pathogen interaction.

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 NKG2C(bright) 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.

NKG2C zygosity influences CD94/NKG2C receptor function and the NK-cell compartment redistribution in response to human cytomegalovirus.

Human cytomegalovirus (HCMV) infection promotes a persistent expansion of a functionally competent NK-cell subset expressing the activating CD94/NKG2C receptor. Factors underlying the wide variability of this effect observed in HCMV-seropositive healthy individuals and exacerbated in immunocompromized patients are uncertain. A deletion of the NKG2C gene has been reported, and an apparent relation of NKG2C genotype with circulating NKG2C(+) NK-cell numbers was observed in HCMV(+) children. We have assessed the influence of NKG2C gene dose on the NK-cell repertoire in a cohort of young healthy adults (N = 130, median age 19 years). Our results revealed a relation of NKG2C copy number with surface receptor levels and with NKG2C(+) NK-cell numbers in HCMV(+) subjects, independently of HLA-E dimorphism. Functional studies showed quantitative differences in signaling (i.e. iCa(2+) influx), degranulation, and IL-15-dependent proliferation, in response to NKG2C engagement, between NK cells from NKG2C(+/+) and hemizygous subjects. These observations provide a mechanistic interpretation on the way the NKG2C genotype influences steady-state NKG2C(+) NK-cell numbers, further supporting an active involvement of the receptor in the HCMV-induced reconfiguration of the NK-cell compartment. The putative implications of NKG2C zygosity over viral control and other clinical variables deserve attention.