Daan Pieren

164 Chapter 6 Moreover, CD69 has been shown to be critical for the generation of memory helper T cells in bone marrow [9]. Slower induction of CD69 expression by T cells may therefore indicate that these T cells egress less efficiently or slower from the blood, which may lead to a delay in the protective immune response. Additionally, induction of CD25 expression is required for formation of the high- affinity IL-2 receptor together with CD122 and CD132, which is a driving factor of T-cell proliferation once in contact with IL-2 [10]. Reduced expression of CD25 may therefore explain impaired T-cell proliferation. Lastly, proliferation of T cells as a result of stimulation (e.g. primary response to foreign antigen) is not only vital for the formation of protective T-cell memory, but also to maintain protection during secondary pathogen encounter [11]. A decline of the capacity of T cells to proliferate may therefore influence both the expansion in the presence of a novel antigen, as well as the memory T-cell response, which may lead to susceptibility to infectious diseases and reduced responses to vaccination at older age. Thus, in the light of viral infections, slower T-cell responses may facilitate rapid viral replication and infection, ultimately leading to decreased protection and more prolonged and/or severe disease. Novel Markers for Human CD8 + T-cell Aging: TIGIT and Helios The gradual loss of co-stimulatory receptors CD28 and CD27 has previously been linked to differentiation of CD8 + T cells as a consequence of chronic or latent viral infections [12] and aging [13-15]. The current view is that early- differentiated CD27 + CD28 + CD8 + T cells convert to intermediate-differentiated CD27 + CD28 - cells, before reaching the CD27 - CD28 - late-differentiation stage due to repeated activation. Late-differentiated cells are currently regarded senescent T cells due to their impaired proliferation, expression of senescence- associated markers CD57 and killer cell lectin-like receptor G1 (KLRG1), and presence of shortened telomeres [13,15]. Due to these findings, research on T-cell senescence has therefore mainly focused on late-differentiated cells. In chapter 4 , we identify that co-expression of TIGIT and Helios, two recently described immunosuppression-markers, can be used as a marker for immunosenescent CD8 + T cells, as TIGIT + Helios + cells showed a trend towards higher expression of CD57 and KLRG1, and functionally showed impaired capacity to proliferate and activate. Interestingly, we found these cells not only accumulating in the late-differentiated T-cell subset at old age, but also to accumulate within the intermediate-differentiated T-cell subset of older adults. The importance of the intermediate-differentiated CD8 + T-cell subset is only recently becoming more apparent, as it has been shown that elevated numbers of the intermediate subset can be used as a biomarker that predicts frailty [16], although the phenotype of