Large cytomegalovirus (CMV)-specific CD8 T-cell responses are observed in both young and, somewhat more often, old people. Frequent CMV reactivation is thought to exhaust these cells and render them dysfunctional so that larger numbers of them are needed to control CMV. Expansions of CMV-specific CD4 T cells are also seen but are less well studied. In this study, we examined the T-cell response to the dominant CMV pp65 and IE-1 antigens in healthy CMV-infected people across a wide age range (

Background. Cytomegalovirus (CMV) infection directly targets vascular endothelium and smooth muscle and at older ages is associated with accelerated vascular pathology and mortality. CMV-specific cellular immunity might directly contribute to this process.Methods. Conventional ex vivo activation–induced T-cell responses to 19 dominant CMV antigens, along with CMV-specific inducible regulatory-type CD4+ T cells (iTregs), were measured in healthy older people, using a novel protocol that included classic Treg markers alongside the activation marker CD134. Measurements were correlated with diastolic, systolic, and mean arterial blood pressure, a surrogate marker for arterial stiffness.Results. CMV-specific iTregs recognized the same antigens as conventional CD4+ T cells and were significantly more frequent at older ages. They suppressed antigen-specific and nonspecific proliferation and in large part expressed Foxp3. Frequencies of CMV-specific iTregs and CD8+ T cells (summated response) were significantly associated with diastolic and mean arterial pressures. Confounders, including age, body mass index, smoking, antihypertensive medication use, or C-reactive protein levels, did not explain these observations.Conclusions. A novel CMV-induced regulatory-type CD4+ T-cell subset is readily detectable in CMV-infected people and, like the aggregate CD8+ T-cell response to the most dominant CMV antigens, is quantitatively associated with arterial stiffness in older life. Whereas CD8+ effector T cells might directly cause vascular injury, iTregs may attenuate this response.

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Background. Parallel upregulation of several T-cell effector functions (ie, polyfunctionality) is believed to be critical for the protection against viruses but thought to decrease in large T-cell expansions, in particular at older ages. The factors determining T-cell polyfunctionality are incompletely understood. Here we revisit the question of cytomegalovirus (CMV)–specific T-cell polyfunctionality, including a wide range of T-cell target proteins, response sizes, and participant ages.Methods. Polychromatic flow cytometry was used to analyze the functional diversity (ie, CD107, CD154, interleukin 2, tumor necrosis factor, and interferon γ expression) of CD4+ and CD8+ T-cell responses to 19 CMV proteins in a large group of young and older United Kingdom participants. A group of oldest old people (age >85 years) was included to explore these parameters in exceptional survivors. Polyfunctionality was assessed for each protein-specific response subset, by subset and in aggregate, across all proteins by using the novel polyfunctionality index.Results. Polyfunctionality was not reduced in healthy older people as compared to young people. However, it was significantly related to target protein specificity. For each protein, it increased with response size. In the oldest old group, overall T-cell polyfunctionality was significantly lower.Discussion. Our results give a new perspective on T-cell polyfunctionality and raise the question of whether maintaining polyfunctionality of CMV-specific T cells at older ages is necessarily beneficial.

Body mass index (BMI) is a known risk factor for cardiovascular disease and cancer. It is also related to white blood count (WBC) and inflammation. The effects of age and gender on these associations have not been explored. Here we have examined the relationships between BMI and inflammatory parameters/cardiovascular risk factors including WBC/neutrophil count (NC), CRP and mean arterial blood pressure (MAP), in young (20-35 years) and older (60-85 years) healthy donors with respect to gender and CMV IgG serology. In young but not older people significant associations between BMI and WBC were observed, however, with opposite directions in the two genders. Only in CMV+ older women a positive trend was preserved. Across the population, there was no significant association between NC and MAP; however, among older men we saw a positive correlation between the two parameters. Linear regression confirmed that across the whole population, age group (young versus older) and also the interaction between gender and age group but not gender alone had significant effects on this association. When analysing CMV+ older people separately we established that both NC and its interaction with gender had a significant effect on MAP. This study reveals that the correlations between common inflammatory markers/cardiovascular risk factors depend on age, gender, and CMV status in a complex fashion. Our findings support the need to evaluate risk factors independently in men and women and to take into account CMV infection status. More focused studies will be required to shed light on these novel findings.