Cytomegalovirus Seropositivity Predicts a Decline in the T Cell But Not the Antibody Response to Influenza in Vaccinated Older Adults Independent of Type 2 Diabetes Status

Abstract

Type 2 diabetes mellitus (T2DM) and persistent cytomegalovirus (CMV) infection are postulated contributors to inflammatory processes that impact on the age-related decline in T-cell responses to influenza vaccination. Older subjects with T2DM (n = 30) and healthy aged controls (n = 40) were enrolled and received influenza vaccination in this study. Serum inflammatory markers and CMV serostatus were measured. Pre- to post-vaccination changes in serum antibody titers to the A/H3N2 strain, and levels of granzyme B (GrB, cytotoxic T lymphocytes) in lysates and cytokines in supernatants from influenza A/H3N2-challenged peripheral blood mononuclear cells were measured. We found no difference between the T2DM and healthy groups in the immune responses measured. However, CMV serostatus was a key determinant of the GrB response to influenza challenge; CMV+ subjects had low levels of inducible GrB (iGrB) activity in response to influenza challenge. In contrast, the serum antibody response to the A/H3N2 vaccine strain did not differ with CMV serostatus, and serum levels of the inflammatory marker, β2-microglobulin, were positively correlated with age, T2DM, and serum IL-10 levels. In conclusion, CMV seropositivity associated with a decline in GrB responses to influenza may predict increased susceptibility to influenza in older adults.

How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms?

“…CMV serostatus has been shown to be a key determinant of the Granzyme B (GrB) response to influenza challenge; CMV-seropositive subjects had low levels of inducible GrB activity in response to influenza challenge (Haq et al 2016), suggesting that CMV seropositivity associated with a decline in GrB responses to influenza may predict increased susceptibility to influenza in older adults. CMV seropositivity has also been shown to induce the expansion of polyfunctional CD8+ T cells (CD8+CD57+) secreting multiple cytokines (IFN-γ, TNF-α), which can degranulate in response to stimulation, and are therefore crucial for the generation of optimal responses to infections and vaccines (Pera et al 2014).…”

Influenza vaccine-mediated protection in older adults: Impact of influenza infection, cytomegalovirus serostatus and vaccine dosage

“…Inconsistent findings of the impact of CMV on antibody responses to vaccination have been reported (Wald et al, 2013; Frasca et al, 2015; Furman et al, 2015; McElhaney et al, 2015; Haq et al, 2016). While the influenza B GMT was higher pre-vaccination in CMV − subjects, there was no difference in GMT fold increase (Fig.…”

“…We have previosuly shown that GrB levels in unstimulated T-cells (bGrB) are higher is CMV + compared to CMV − older adults (McElhaney et al, 2012; Haq et al, 2016) possibly due to continued activation of CMV-specific T-cells to maintain CMV latency. This study mirrors the previous studies (Fig.…”

“…The majority of older adults are seropositive for cytomegalovirus (CMV) (Staras et al, 2006) which may be a confounding factor in evaluating the immune response to influenza vaccination (Frasca et al, 2015; Furman et al, 2015; McElhaney et al, 2015; Haq et al, 2016). Persistent CMV infection has been shown to be a major driver of terminal differentiation of CD8 + T-cells (Derhovanessian et al, 2009; McElhaney et al, 2009).…”

“…These terminally differentiated CD8 + T-cells express and release the cytolytic mediator, GrB, in the absence of perforin in both the resting and activated state (Zhou and McElhaney, 2011), and can contribute to toxicity in the extracellular space (McElhaney et al, 2012). The presence of high levels of baseline GrB (bGrB) in the resting state of unstimulated T-cells hinders the inducible GrB (iGrB) response to ex vivo influenza challenge (McElhaney et al, 2012; Haq et al, 2016) and may result in a compromised response to infection.…”