AGING WITH T CELLS: The Rise of Regulatory T-cell Features at Older Age

During aging, the immune system undergoes changes that bring the tightly regulated immune system out of balance. The age-related changes to the immune system have collectively been termed ‘immunosenescence’. As a consequence of immunosenescence, the risk of acquiring infectious diseases and the course of disease is prolonged and more severe at old age. T cells are imperative for protection against pathogens and various molecules on different subsets of T cells are involved in maintaining a balanced immune system. T cells express molecules that initiate cellular activation and proliferation, but there are also molecules that act as a breaking mechanism on these responses to prevent over-activation. During aging, this system becomes dysregulated. To explain reduced response to vaccination, susceptibility to infectious disease, and increased disease severity observed at older age, it is crucial to identify the underlying age-related changes of T cells. In this thesis, we set out to identify novel age-related changes of the T-cell population in mice and humans that may contribute to understanding the impact of aging on T cells. We investigate T-cell phenotype, responses, and proliferation in both mice and humans under healthy conditions and during respiratory viral infection in humans. In mice and humans we found that the activation and proliferation of several T-cell subsets slow down at older age. These findings may serve as a new hallmark of T-cell aging and contribute to understanding the reduced response of T cells after vaccination or infection. Additionally, we report an upsurge of regulatory T-cell frequencies in older wildtype mice. Using a mouse model for the accumulation of DNA damage (Ercc1-deficient mice), we found that the accumulation of regulatory T cells with age may in part be explained by the accumulation of DNA damage with age. Furthermore, we show that T cells with regulatory functions also accumulate in humans. We discovered a novel CD8+ T-cell subset with immunosuppressive capacities, which we named KIR+RA+ T cells based on their expression of KIR and CD45RA. We found KIR+RA+ T cells to be highly activated in (older) individuals that are suffering from respiratory viral infection, including Influenza A virus and the novel SARS-CoV-2. Importantly, activation of KIR+RA+ T cells was associated with prolonged presence of symptoms in older adults infected with Influenza A virus, indicating that these regulatory KIR+RA+ T cells may aggravate respiratory disease following viral infection, possibly by suppressing anti-viral CD8+ T cells. Our findings highlight the importance of studying the altered response kinetics of T cells at older age and the rise of regulatory-cell features in the T-cell population, which both may contribute to impaired protective immunity against infectious diseases in older individuals. Ultimately, these fundamental findings may provide new starting points for other fundamental, translational, and clinical studies that focus on vaccination of older adults, infectious disease resistance, and healthy aging