Daan Pieren

16 Chapter 1 cells secrete a range of inflammatory cytokines (e.g. tumor necrosis factor alpha (TNF- α ) and IL-6) collectively called the senescence-associated secretory phenotype (SASP) [86,87]. Within the field of T-cell immunology and aging, accumulation of senescent T cells is thought to partly explain reduced T-cell protective responses in older adults. As a way to identify senescent T cells, both CD4 + and CD8 + T cells have previously been stratified into three differentiation stages based on their expression of co-stimulatory receptors CD27 and CD28 [88]. CD8 + T cells lose CD27 and CD28 expression during aging as these cells convert from CD27 + CD28 + early-differentiated cells to CD27 + CD28 - intermediate-differentiated cells and, finally, into CD27 - CD28 - late-differentiated T cells [88-91], which are thought to be senescent T cells. Late-differentiated CD27 - CD28 - cells show reduced proliferation and responsiveness [88,92,93], which are two vital processes for the maintenance and protective ability of adaptive immune responses. Moreover, several alterations have been reported within these cells that can be linked to impaired functionality of these cells, such as increased expression of the senescence marker p16 [94], increased presence of DNA damage [93,95,96], and shortened telomeres [91]. T-cell Exhaustion Expression of co-inhibitory receptors on CD8 + T cells is extensively being studied in the T-cell aging field as it is thought that increased expression of these receptors may account for the decline of CD8 + T-cell responses with age. T-cell ‘exhaustion’ was initially coined in the context of chronic viral infections in mice [97] and was later linked to sustained expression of co-inhibitory receptors [98]. Exhausted T cells show a gradual loss of function which is thought to develop through high- and/or chronically present antigen load to which T cells respond [85,99]. Discovery of novel (combination of) T-cell exhaustion and inhibitory markers and insight into their role during aging is important to explain the decline of T-cell responses with age. PD-1 is one of the most well-known co-inhibitory markers that reduces T-cell proliferation and effector functionality [100]. The first study that strikingly showed the importance of PD-1 in mice showed that during an acute infection, PD-1 is highly upregulated on T cells and was required to prevent overt inflammatory response, after which PD-1 expression was downregulated [101]. However, chronic infection leads to sustained expression of PD-1, and thereby limits the protective response [101]. In mice it was discovered that aging promotes the accumulation of PD-1-expressing cells [102-105]. Most likely, existence of exhausted cells over the course of aging in mice is due to