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Dynamic Changes in Natural Killer Cell Subset Frequencies in the Absence of Cytomegalovirus Infection.

ABSTRACT: Individuals lacking functional natural killer (NK) cells suffer severe, recurrent infections with cytomegalovirus (CMV), highlighting the critical role of NK cells in antiviral defense. Therefore, ongoing attempts to develop an efficacious vaccine to prevent CMV infection should potentially aim to elicit NK-cell antiviral responses as an accessory to conventional T- and B-cell based approaches. In this regard, CMV infection provokes marked phenotypic and functional differentiation of the NK-cell compartment, including development of adaptive NK cells that exhibit enhanced antiviral activity. We examined longitudinal blood samples collected from 40 CMV-seronegative adolescents to ascertain whether a CMV glycoprotein B (gB) vaccine in the absence of CMV infection can stimulate differentiation or expansion of CMV-associated subsets of NK cells. Study participants uniformly lacked the CMV-dependent NKG2C+ subset of NK cells, suggesting that an adjuvanted CMV gB vaccine alone is an inadequate stimulus for sustained expansion of these cells. In contrast, we observed unexpected dynamic fluctuations in the frequency of NK cells lacking FcR?, EAT-2, and SYK, which were independent of vaccination or CMV infection. Whereas, FcR?neg NK cells in CMV infection are reported to express increased levels of the maturation marker CD57, the FcR?neg NK cells observed in our CMV-negative vaccine cohort express less CD57 than their FcR?+ counterparts. The FcR?neg NK cells in CMV-negative individuals were also functionally distinct from this subset in CMV infection, exhibiting comparable IFN-? production and degranulation as FcR?+ NK cells in response to cytokine or antibody-dependent stimuli. These results suggest that frequencies of some NK cell subsets may increase in response to unknown environmental or inflammatory cues distinct from that which occurs after CMV infection. Greater understanding of the nature of the signals driving CMV-independent accumulation of these subsets should permit development of mechanisms to facilitate vaccine-driven expansion of CMV-reactive NK cells.

SUBMITTER: Gyurova IE

PROVIDER: S-EPMC6882915 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Dynamic Changes in Natural Killer Cell Subset Frequencies in the Absence of Cytomegalovirus Infection.

Gyurova Ivayla E IE Schlums Heinrich H Sucharew Heidi H Ambroggio Lilliam L Ochayon David E DE Win Hannah Than HT Bryceson Yenan T YT Bernstein David I DI Waggoner Stephen N SN

Frontiers in immunology 20191122

Individuals lacking functional natural killer (NK) cells suffer severe, recurrent infections with cytomegalovirus (CMV), highlighting the critical role of NK cells in antiviral defense. Therefore, ongoing attempts to develop an efficacious vaccine to prevent CMV infection should potentially aim to elicit NK-cell antiviral responses as an accessory to conventional T- and B-cell based approaches. In this regard, CMV infection provokes marked phenotypic and functional differentiation of the NK-cell ...[more]

PMID: 31824507

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Project description:BackgroundCytomegalovirus establishes lifelong persistency in the host and leads to life threatening situations in immunocompromised patients. FoxP3+ T regulatory cells (Tregs) critically control and suppress innate and adaptive immune responses. However, their specific role during MCMV infection, especially pertaining to their interaction with NK cells, remains incompletely defined.MethodsTo understand the contribution of Tregs on NK cell function during acute MCMV infection, we infected Treg depleted and undepleted DEREG mice with WT MCMV and examined Treg and NK cell frequency, number, activation and effector function in vivo.ResultsOur results reveal an increased frequency of activated Tregs within the CD4+ T cell population shortly after MCMV infection. Specific depletion of Tregs in DEREG mice under homeostatic conditions leads to an increase in NK cell number as well as to a higher activation status of these cells as compared with non-depleted controls. Interestingly, upon infection this effect on NK cells is completely neutralized in terms of cell frequency, CD69 expression and functionality with respect to IFN-? production. Furthermore, composition of the NK cell population with regard to Ly49H expression remains unchanged. In contrast, absence of Tregs still boosts the general T cell response upon infection to a level comparable to the enhanced activation seen in uninfected mice. CD4+ T cells especially benefit from Treg depletion exhibiting a two-fold increase of CD69+ cells 40 h and IFN-?+ cells 7 days p.i. while, MCMV infection per se induces robust CD8+ T cell activation which is also further augmented in Treg-depleted mice. Nevertheless, the viral burden in the liver and spleen remain unaltered upon Treg ablation during the course of infection.ConclusionsThus, MCMV infection abolishes Treg suppressing effects on NK cells whereas T cells benefit from their absence during acute infection. This study provides novel information in understanding the collaborative interaction between NK cells and Tregs during a viral infection and provides further knowledge that could be adopted in therapeutic setups to improve current treatment of organ transplant patients where modulation of Tregs is envisioned as a strategy to overcome transplant rejection.

Dataset Information

Dynamic Changes in Natural Killer Cell Subset Frequencies in the Absence of Cytomegalovirus Infection.

Publications

Dynamic Changes in Natural Killer Cell Subset Frequencies in the Absence of Cytomegalovirus Infection.

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