Sara van den Berg

1 11 General introduction AGEING OF THE IMMUNE SYSTEM: IMMUNOSENESCENCE The worldwide population is ageing rapidly. In 2050, one in six people in the world will be over the age of 65, while in 2019 this was still one in eleven individuals. An increase in the proportion of older adults poses important public health challenges. With age, new diseases arise. The immune system is no exception to this: as ‘Immunological resistance’ wanes with age, susceptibility for auto-immunity, cancer and infectious diseases increase with age [1-3]. Specifically respiratory infections cause a large disease burden in older adults, with influenza inducing most morbidity and mortality [4]. Ageing of the immune system is often popularly termed ‘immunosenescence’. Although the use of the term immunosenescence differs between researchers, a strict definition contains an age-related functional impairment of the immune system. This entails a decreased response to infectious diseases as well as a diminished vaccine response in older adults. Paradoxically, the means by which we aim to provide protection to infectious diseases in the elderly, vaccination, thus also declines in effectiveness with age. This results in suboptimal protection of an already vulnerable population. HALLMARKS OF T-CELL CHANGES WITH AGE Characteristics of ageing of the immune system are well-described and primarily affect the adaptive immune system, specifically the composition of the T-cell pool. The production of naive T-cells by the thymus decreases dramatically with age [5]. As a result of this, and because naive T-cells are gradually recruited into the memory T-cell pool, naive T-cells decrease in number with age [6, 7]. This will likely affect de novo immune responses in aged individuals. In contrast, memory T-cells increase in number because of antigen challenges with different pathogens during life. Memory T-cells are heterogeneous and can be divided into distinct differentiation states. In older individuals, more memory T-cells are of the ‘late- stage differentiated phenotype’ and express higher levels of so-called senescence-associated markers, including the markers CD57 and KLRG-1 [8]. This expression pattern is indicative of T-cells lacking the ability to proliferate, and therefore these cells are thought to respond less well to recall immune challenges [8, 9]. Furthermore, the overall diversity of T-cells, marked by specific T-cell receptors, is thought to decrease with age [10, 11] causing a less broad immune response at old age [12]. Large clonal expansions of memory T-cells, consisting of a lot of cells expressing identical T-cell receptors, are more abundant in older adults. These changes are predominantly present in the CD8 + T-cell pool, but have also been observed in the CD4 + T-cell pool. Overall, these changes in the T-cell pool that appear with age are thought to contribute to a large extent to reduced protection to infectious diseases and reduced vaccine responses in older adults. Immunosenescence is thereby contributing to increased mortality at older age. CMV-ENHANCED IMMUNOSENESCENCE: THE RISE OF A THEORY In the early 2000s, two longitudinal studies [13, 14] from Sweden were published that formed the basis of a new theory: the ability of latent cytomegalovirus (CMV) infection to enhance immunosenescence. CMV is a common herpes virus, characterized by life-long persistence