Daan Pieren

162 Chapter 6 Identification of changes that T cells undergo during aging may provide new insights and starting points for fundamental T-cell research and for future therapeutic strategies in older patients which may improve health in the elderly. This thesis focusses on the fundamentals of changes that occur to T cells during aging in both mice and humans. We provide new leads to explain decreased immune protection in the elderly. In mice and humans we found that the kinetics of T-cell responses slow down at older age. Moreover, we report an upsurge of expression of regulatory T-cell features with age and we discovered a novel CD8 + T-cell subset with immunosuppressive capacities, which we named KIR + RA + T cells. AGING RESULTS IN DISTINCT CHANGES OF T-CELL RESPONSES T-cell Response Kinetics are a Hallmark of Immune Aging Changes that T cells undergo during aging are often addressed by assessing the ex vivo phenotype of T cells and/or measuring the in vitro T-cell response at a single point in time. However, insight into the impact of aging on the kinetics of the T-cell response over several days is limited [1,2]. An example that emphasizes the importance of timely and robust T-cell responses is the ongoing SARS- CoV-2 pandemic. Symptomatic and asymptomatic individuals that suffered from COVID-19 produced IgG antibodies in response to SARS-CoV-2, but these antibody levels declined rapidly within the following two to three months [3,4]. Disappearance of IgG antibodies removes a protective immunological barrier and increases the chance of secondary SARS-CoV-2 infection. In the absence of this line of defense, the need for a rapid T-cell response is vital to prevent viral dissemination throughout the lung. Importantly, the need for a rapid T-cell response does not only apply to SARS-CoV-2 infection, but also infection with respiratory viruses such as influenza virus and RSV. Expansion and activation of naive T cells to form a memory T-cell subset that is directed against respiratory viruses, ready to act upon secondary exposure is a highly important process to provide immediate protection, as well as future protection. Delay in T-cell activation and proliferation as a consequence of aging may therefore lead to impaired generation and maintenance of T-cell memory and removal of infected lung cells, allowing viral dissemination and resulting in more severe disease. In chapter 2 we investigated the impact of aging on the kinetics of T-cell responses in young and aged mice and conclude that these response kinetics are an important factor to address in T-cell aging research. We measured expression of the classical activation markers CD25 and CD69 [5,6] on T-cell