Cytomegalovirus-associated accumulation of late-differentiated CD4 T-cells correlates with poor humoral response to influenza vaccination
Highlights
► Influenza vaccination is less effective in CMV-seropositive elderly than young. ► CD8+CD28− T-cells are not associated with poor humoral vaccine responses. ► CD45RA+CCR7−CD27−CD28−CD4+ T-cells accumulate in CMV-seropositive individuals. ► CD45RA+CCR7−CD27−CD28−CD4+ cells are associated with poor humoral vaccine responses.
Introduction
Seasonal influenza is a disease with serious clinical and economic burdens, estimated to be the cause of an average of 226,000 hospitalizations and 36,000 deaths per season between 1979 and 2001 in the United States, with 90% of deaths occurring in individuals over the age of 65 [1], [2]. Annual influenza vaccination is the most effective method for preventing influenza and its complications [3]. However, exactly the group most susceptible to influenza morbidity and mortality, the elderly, does not respond as well as the young to vaccination. While in the young, the clinical vaccine efficacy is estimated at 70–90%, this corresponds to only 17–53% in the elderly, depending on the vaccine matching with the viruses in circulation [4]. This is widely believed to be due to immunosenescence, the diminished state of the immune system observed in the elderly [5], [6].
The specific mechanisms responsible for the decreased ability of the elderly to respond to influenza vaccination are still poorly understood. CD8+ T-cells lacking the costimulatory receptor CD28 have been associated with poor humoral and cellular response to influenza vaccination in the elderly [7], [8], [9]. CD28 down-regulation is the result of several rounds of T-cell division in response to antigenic challenge. Thus, CD8+ T-cells specific for chronic antigens, such as human immunodeficiency virus (HIV), cytomegalovirus (CMV) and to a lesser extent Epstein–Barr virus (EBV) lack the expression of this receptor [10], [11], [12]. CMV is an almost-ubiquitous β-herpes virus present in 30–90% of the population in developed countries with a rising seroprevalence with increasing age [13]. Although asymptomatic in immunocompetent individuals, it has an enormous impact on the immune system of the host – more than 30% of CD4+ and CD8+ T-cells of a healthy middle-aged individual can be specific for this virus [14]. A latent CMV infection is associated with lower levels of naïve T-cells and accumulation of memory T-cells, both hallmark features of immunosenescence [15], [16], [17], [18]. This has led to the increasingly accepted notion that CMV accelerates T-cell immunosenescence [19]. Accordingly, CMV has been associated with poor humoral response to influenza vaccination in the elderly in some [20], [21], but not all studies [22].
Thus, if and how CMV-seropositivity and the accumulation of CD28− late-differentiated T-cells associated with it contribute to poor vaccination outcome in the elderly is still unclear. The few studies demonstrating a negative correlation between CD28−CD8+ T-cells and poor vaccination outcome [7], [8], [9] did not take CMV-serostatus into account, thus failing to demonstrate a direct link between accumulation of these cells and poor responsiveness to influenza vaccine.
Here we have correlated the detailed phenotype of circulating CD4+ and CD8+ T-cell subsets with humoral responses in young and old individuals receiving Intanza, an intradermal influenza vaccine specially designed for the elderly [23]. Our data demonstrate a negative impact of the presence of CD4+ but not CD8+ T-cells with a more late-differentiated phenotype on responsiveness to the vaccine in individuals over the age of 60. This suggests that the negative impact of CMV on vaccination outcome, observed in our study, might be mediated through CD4 T-cells lacking the expression of CCR7, CD27 and CD28 and re-expressing CD45RA.
Section snippets
Study population and design
The current study was embedded in an open-label uncontrolled multicenter phase III trial (UTN U1111-1112-2795) that evaluated the humoral immunogenicity and safety of the Northern Hemisphere 2010–2011 formulation of an intradermal inactivated split-virion influenza vaccine (Intanza®, Sanofi Pasteur) in adults (18–59 yr) and elderly (>60 yr), as required for marketing authorization. Participants at the University of Antwerp were invited after the last visit of the clinical trial (June–July 2010)
CMV serostatus
All subjects were CMV IgM-negative, whereas 26 were CMV IgG-positive. Prevalence of CMV-seropositivity was higher in >60 year-olds than in younger participants (Table 1), but not related to age within the former group (Table 2).
Anti-vaccine humoral responses in vivo
Three weeks after vaccination, anti-influenza humoral responses were detected in 41/54 of study subjects (76%). The response rate was significantly higher in individuals <60 yr of age (96%) compared to >60 yr (60.0%, p = 0.003, Table 1). This was true for responsiveness to
Discussion
Influenza vaccination is less effective in the elderly compared to the young. Identifying immune parameters that differ between responders and non-responders will assist in development of better, more effective vaccines in the elderly or define screening policies for adapted immunization. CD28−CD8+ T-cells have been reported to correlate with poor vaccination outcome in the elderly in three studies [7], [8], [9]. Despite the fact that the frequency of these cells is directly associated with
Role of the funding source
This work was supported by the European Commission [FP7 259679 “IDEAL”]; German Research Foundation [DFG-PA 361/14-1]; German Federal Ministry of Education and Research [BMBF 0315890F, “Gerontoshield”] and the Methusalem funding program of the University of Antwerp (22858). NC and HD are postdoctoral fellows of the Fund for Scientific Research (FWO)-Flanders. The funding sources were not involved in study design; in the collection, analysis and interpretation of data; in the writing of the
Author's contributions
ED contributed to study design, analysis and interpretation of the data. HD, PVD and NC were involved in the conceptual design of the study, carried out the clinical trial and generated the serological data. KH contributed to generation and analysis of the flow cytometry data. GP contributed to study design and interpretation of the results. All authors were involved in drafting the manuscript and have approved the submitted version.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgements
We would like to thank Prof. Hans-Peter Pircher (University of Freiburg) for providing the anti-KLRG-1 primary antibody, Lilly Oettinger for antibody titration and flow cytometry quality control and Kevin Lenders for processing the blood samples.
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