Changes to the Natural Killer Cell Repertoire after Therapeutic Hepatitis B DNA Vaccination

T Mark Doherty,Daniel Scott-Algara,Stanislas Pol,Hélène Fontaine,Maryline Mancini-Bourgine,Marie-Louise Michel

doi:10.1371/journal.pone.0008761

T Mark Doherty, Daniel Scott-Algara + Show 4 more

Open Access

https://doi.org/10.1371/journal.pone.0008761

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Abstract

BackgroundImprovements to the outcome of adaptive immune responses could be achieved by inducing specific natural killer (NK) cell subsets which can cooperate with dendritic cells to select efficient T cell responses. We previously reported the induction or reactivation of T cell responses in chronic hepatitis B patients vaccinated with a DNA encoding hepatitis B envelope proteins during a phase I clinical trial.Methodology/Principal FindingsIn this study, we examined changes in the peripheral NK cell populations occurring during this vaccine trial using flow cytometry analysis. Despite a constant number of NK cells in the periphery, a significant increase in the CD56bright population was observed after each vaccination and during the follow up. Among the 13 different NK cell markers studied by flow cytometry analysis, the expression of CD244 and NKG2D increased significantly in the CD56bright NK population. The ex vivo CD107a expression by CD56bright NK cells progressively increased in the vaccinated patients to reach levels that were significantly higher compared to chronically HBV-infected controls. Furthermore, modifications to the percentage of the CD56bright NK cell population were correlated with HBV-specific T cell responses detected by the ELISPOT assay.Conclusions/SignificanceThese changes in the CD56bright population may suggest a NK helper effect on T cell adaptive responses. Activation of the innate and adaptive arms of the immune system by DNA immunization may be of particular importance to the efficacy of therapeutic interventions in a context of chronic infections.Trial RegistrationClinicalTrials.gov NCT00988767

Highlights

Natural Killer (NK) cells have recently been identified as crucial actors of innate host immunity in response to a variety of pathological challenges [1]
Within natural killer (NK) cells, a significant increase in the proportion of CD56bright NK cells defined as CD56bright CD16- was observed one month after the first (M1 vs. M0, p,0.02) and second (M3 vs. M2, p,0.02) vaccine injections, suggesting that this population was triggered by DNA vaccination (Fig. 1A, middle panel)
Percentage of CD56bright NK cells expressing CD244, CD161, NKG2D or CD107a marker is shown for individual patients

Summary

Introduction

Natural Killer (NK) cells have recently been identified as crucial actors of innate host immunity in response to a variety of pathological challenges [1]. Their role in controlling pathogenesis induced by infection is dual and can occur through both cytokine/ chemokine secretion and antibody dependent or natural cytotoxic activity toward infected target cells. NK cells express several families of receptors including both inhibitory and activating receptors [1]. Improvements to the outcome of adaptive immune responses could be achieved by inducing specific natural killer (NK) cell subsets which can cooperate with dendritic cells to select efficient T cell responses. We previously reported the induction or reactivation of T cell responses in chronic hepatitis B patients vaccinated with a DNA encoding hepatitis B envelope proteins during a phase I clinical trial

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