Daan Pieren

143 Regulatory KIR+RA+ CD8+ T cells accumulate with age event of COVID-19 caused by SARS-CoV-2 infection. Only a minority (up to 20%) of individuals are expected to have a small fraction of cross-reactive antigen- specific memory CD8 + T cells directed against this virus, which further supports a bystander role for KIR + RA + T cells [60]. The exact factors inducing bystander activation remain to be elucidated, but IL-15 has been implicated [22]. Together, our findings suggests that the accumulation of KIR + RA + T cells with age may play a significant role in a wide range of respiratory viral infections. To understand the in vivo clinical relevance of KIR + RA + T cells, we analyzed the presence and dynamics of activation of these cells in older adults suffering from respiratory viral infection. Our findings show that KIR + RA + T cells become a highly activated T-cell subset during respiratory infections caused by various viruses. It has been shown previously that coughing associates with increased viral load in the lungs [61]. We observed a positive correlation between the level of activated KIR + RA + CD8 +  T cells and duration of coughing, which may suggest hampered clearance of infected lung cells. As cytotoxic CD8 + T cells clear virally infected cells and thereby reduce the severity of disease [13-16], suppression of their responses by KIR + RA + T cells may prolong illness. Indeed, CD4 + Tregs have been reported to suppress CD8 + effector cells in influenza A infected mice [62]. Recently, a function of TIGIT was identified in the prevention of pathological tissue damage in an infectious disease setting [63]. This suggests that TIGIT Hi KIR + RA + T cells may also be advantageous in preventing excessive lung damage. Therefore, the role of KIR + RA + T cells may be two-sided: they may be needed to limit lung damage caused by cytotoxic immune cells, whereas an overrepresented activation of KIR + RA + T cells may hamper effective clearance of pathogens. Establishing correlates of respiratory disease is highly important for developing strategies to reduce the burden of disease following respiratory infections as elderly are at higher risk of severe disease, hospitalization, and death (reviewed in [4]). Our findings indicate that KIR + RA + T cells may serve as such a correlate of respiratory disease. Moreover, our findings warrant future investigation on elucidating their immunoregulatory mechanisms as well as their role at the site of infection. In summary, our findings support a model for declining CD8 + T-cell responses with age where accumulation of regulatory KIR + RA + T cells may in part determine the outcome of protective T-cell responses against respiratory infection. These cells may therefore serve as target for new preventive or therapeutic strategies. 5