Development of the adaptive NK cell response to human cytomegalovirus in the context of aging

López‐Botet, Miguel; Muntasell, Aura; Martínez-Rodríguez, José Enrique; López-Montañés, María; Costa‐García, Marcel; Pupuleku, Aldi

doi:10.1016/j.mad.2016.06.010

Cited by 12 publications

(13 citation statements)

References 45 publications

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“…Our results show that CMV seropositivity in young individuals associates with a significant increase in the percentage of CD56 dim NK cells expressing Eomes and a decreased percentage of T-bet hi NK cells within the CD56 dim CD57 + subset, suggesting that changes in the expression of these transcription factors are involved in CMV-induced remodeling of NK cells, characterized by the expansion of CD56 dim CD57 + NK cells coexpressing NKG2C activating receptors (2, 14, 30, 60, 79). It has been reported that the level of expression of Eomes and T-bet is strongly reduced in NK cells from allogeneic hematopoietic stem cell transplantation recipients compared with healthy control subjects and that acute graft-versus-host disease and CMV reactivation are associated with further downregulation of T-bet (80) supporting the importance of these transcription factors in the generation and differentiation of NK cells and in the response against CMV after hematopoietic stem cell transplantation.…”

Section: Discussionmentioning

confidence: 72%

“…These cells have some characteristics of adaptive immunity and are considered “memory” or “adaptive” NK cells (55–58). The magnitude of the expansion of NKG2C high NK cells is determined by the magnitude of the proinflammatory cytokine secretion upon NK cell activation (59), and it has been proposed that these cells contribute to the proinflammatory environment based on the relation between the percentage of NKG2C + cells, elevated levels of PCR, and cardiovascular risk determinants of CMV-seropositive individuals (60, 61). …”

Section: Discussionmentioning

confidence: 99%

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Effect of CMV and Aging on the Differential Expression of CD300a, CD161, T-bet, and Eomes on NK Cell Subsets

et al. 2016

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Natural killer (NK) cells are innate lymphoid cells involved in the defense against virus-infected cells and tumor cells. NK cell phenotype and function is affected with age and cytomegalovirus (CMV) latent infection. Aging affects the frequency and phenotype of NK cells, and CMV infection also contributes to these alterations. Thus, a reduction of CD56bright NK cell subpopulation associated with age and an expansion of memory-like NK cells CD56dimCD57+NKG2C+ probably related to CMV seropositivity have been described. NK cells express T-bet and Eomes transcription factors that are necessary for the development of NK cells. Here, we analyze the effect of age and CMV seropositivity on the expression of CD300a and CD161 inhibitory receptors, and T-bet and Eomes transcription factors in NK cell subsets defined by the expression of CD56 and CD57. CD300a is expressed by the majority of NK cells. CD56bright NK cells express higher levels of CD300a than CD56dim NK cells. An increase in the expression of CD300a was associated with age, whereas a decreased expression of CD161 in CD56dim NK cells was associated with CMV seropositivity. In CD56dim NK cells, an increased percentage of CD57+CD300a+ and a reduction in the percentage of CD161+CD300a+ cells were found to be associated with CMV seropositivity. Regarding T-bet and Eomes transcription factors, CMV seropositivity was associated with a decrease of T-bethi in CD56dimCD57+ NK cells from young individuals, whereas Eomes expression was increased with CMV seropositivity in both CD56bright and CD56dimCD57+/− (from middle age and young individuals, respectively) and was decreased with aging in all NK subsets from the three group of age. In conclusion, CMV infection and age induce significant changes in the expression of CD300a and CD161 in NK cell subsets defined by the expression of CD56 and CD57. T-bet and Eomes are differentially expressed on NK cell subsets, and their expression is affected by CMV latent infection and aging.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Effect of CMV and Aging on the Differential Expression of CD300a, CD161, T-bet, and Eomes on NK Cell Subsets

et al. 2016

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“…between the levels of % NKG2C + cells and the risk for posttransplant CMV viremia was independent of age. Actually, there is no evidence supporting a relation between aging and the development of adaptive NKG2C + cells in CMV + individuals (32). Despite the limited in vitro direct response of adaptive NK cells against CMV-infected cells, presumably under the influence of viral immune evasion mechanisms, they have been shown to efficiently mediate virus-specific Ab-dependent cytotoxicity and cytokine production triggered through the FcgRIIIa (CD16) receptor (20)(21)(22).…”

Section: Discussionmentioning

confidence: 99%

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

Redondo-Pachón

Crespo

Yélamos

et al. 2017

The Journal of Immunology

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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, NKG2C) 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 patients. Yet, a trend toward increased NKG2C 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.

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“…Expansions of NKG2C + cells following HCMV infection were reported in immunosuppressed transplant recipients ( 65 , 66 , 74 ), in a severe T cell primary immunodeficiency ( 75 ), as well as in children and newborns with congenital or postnatal HCMV infection ( 76 , 77 ), independently of aging ( 78 – 80 ). Altogether, these observations suggest that the magnitude of the HCMV imprint on the NK cell compartment in healthy individuals is likely fixed at the time of primary infection, presumably depending on host/virus genetics and other circumstantial factors (e.g., age at infection, viral load, etc.)…”

Section: Nk Cells and Hcmv Infection In Ktrmentioning

confidence: 99%

“…The frequencies of TcRαβ T cells specific for HCMV antigens (e.g., IE-1 and pp65) have been reported to predict the risk of posttransplant infection ( 109 , 110 ); moreover, TcRγδ T cells were associated with control of posttransplant HCMV viremia ( 111 ). Adaptive NKG2C + NK cells and CTL have been proposed to be independent ( 78 – 80 ). Thus the possibility that the association of adaptive NKG2C + NK cells with a lower risk of HCMV infection might indirectly reflect a central role of HCMV-specific TcRαβ T cells (Figure 3 ) appears unlikely; further studies are warranted to precisely address this issue.…”

Section: Nk Cells and Hcmv Infection In Ktrmentioning

confidence: 99%

Dual Role of Natural Killer Cells on Graft Rejection and Control of Cytomegalovirus Infection in Renal Transplantation

et al. 2017

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Allograft rejection constitutes a major complication of solid organ transplantation requiring prophylactic/therapeutic immunosuppression, which increases susceptibility of patients to infections and cancer. Beyond the pivotal role of alloantigen-specific T cells and antibodies in the pathogenesis of rejection, natural killer (NK) cells may display alloreactive potential in case of mismatch between recipient inhibitory killer-cell immunoglobulin-like receptors (KIRs) and graft HLA class I molecules. Several studies have addressed the impact of this variable in kidney transplant with conflicting conclusions; yet, increasing evidence supports that alloantibody-mediated NK cell activation via FcγRIIIA (CD16) contributes to rejection. On the other hand, human cytomegalovirus (HCMV) infection constitutes a risk factor directly associated with the rate of graft loss and reduced host survival. The levels of HCMV-specific CD8+ T cells have been reported to predict the risk of posttransplant infection, and KIR-B haplotypes containing activating KIR genes have been related with protection. HCMV infection promotes to a variable extent an adaptive differentiation and expansion of a subset of mature NK cells, which display the CD94/NKG2C-activating receptor. Evidence supporting that adaptive NKG2C+ NK cells may contribute to control the viral infection in kidney transplant recipients has been recently obtained. The dual role of NK cells in the interrelation of HCMV infection with rejection deserves attention. Further phenotypic, functional, and genetic analyses of NK cells may provide additional insights on the pathogenesis of solid organ transplant complications, leading to the development of biomarkers with potential clinical value.

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Development of the adaptive NK cell response to human cytomegalovirus in the context of aging

Cited by 12 publications

References 45 publications

Effect of CMV and Aging on the Differential Expression of CD300a, CD161, T-bet, and Eomes on NK Cell Subsets

Effect of CMV and Aging on the Differential Expression of CD300a, CD161, T-bet, and Eomes on NK Cell Subsets

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

Dual Role of Natural Killer Cells on Graft Rejection and Control of Cytomegalovirus Infection in Renal Transplantation

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