Sara van den Berg

90 Chapter 4 INTRODUCTION The worldwide population is ageing rapidly. With age, deleterious changes in the immune system arise, which impair responses against infectious diseases and vaccinations [1, 2]. This phenomenon is referred to as ‘immunosenescence’. Age-related changes of the immune system, such as the increase in CD45RA+ memory T-cells [3, 4] and decreased diversity of the T-cell receptor repertoire [5, 6], are predominantly present in the CD8+ T-cell pool. About 2 decades ago, latent infection with cytomegalovirus (CMV) was implicated as a possible driving force of these age-related changes [7-9]. CMV-seropositivity was identified as part of the so-called ‘immune risk profile’, predictive of early mortality in older adults [9, 10]. Moreover, CMV-seropositivity is the largest non-heritable factor influencing differences among humans in the immune profile [11]. CMV is thought to establish this large effect on the immune system by its frequent attempts to reactivate, thereby gradually affecting the immune system [12]. Since the first signs of CMV-enhanced ageing of the immune system, it is often hypothesized that CMV might impair the immune response to a heterologous challenge [6, 12, 13]. With age, the risk for serious complications and hospitalization after influenza virus infection increases [14]. Vaccination is an important tool to prevent infection and reduce morbidity and mortality. Unfortunately, also the efficacy of influenza vaccination decreases with age, leading to suboptimal protection in older adults [2, 15]. As CMV is thought to contribute to the age-associated decline of the immune system, the role of CMV infection on influenza vaccination efficacy has been well studied and led to conflicting results and both a negative effect of CMV [16-18], as no effect of CMV on the vaccine response [19, 20] has been reported. A systematic review including a meta-analysis of our group showed no clear evidence for a negative effect of CMV infection on the antibody response to influenza vaccination [21]. Both CMV and ageing primarily affect the T-cell compartment. During influenza virus infection, an effect of CMV would therefore mainly be expected on the T-cell response. T-cells play an important role in clearance of influenza virus infection and protection against influenza-related disease [22]. Furthermore, T-cells responses are predominantly specific for the internal viral proteins, which are conserved among antigen drifted influenza strains [23]. Indeed, pre-existing and early influenza virus-specific T-cell responses are associated with lower disease severity of influenza [23, 24], while delayed T-cell responses to influenza are thought to induce prolonged inflammation and delayed viral clearance and recovery [24, 25]. The influenza virus-specific T-cell response is mostly directed against the conserved M1, NP and PA proteins [26]. Upon activation, influenza virus-specific CD8+ T-cells show increased expression of activation and proliferation markers [27, 28], produce proinflammatory cytokines, such as IFN γ and kill virus-infected cells by releasing perforin and granzyme B [26, 29]. In contrast to the attention for influenza vaccination in CMV-enhanced ageing research, the effect of CMV on the immune response to influenza virus infection is less well established.