Daan Pieren

120 Chapter 5 ABSTRACT Aging results in decreased CD8 + T-cell responses leading to increased risk and duration of respiratory infections in the elderly. The great phenotypical diversity of the CD8 + T-cell population has made it difficult to identify the impact of aging on CD8 + T-cell subsets associated with diminished CD8 + T-cell responses. Here we identify a novel human CD8 + T-cell subset characterized by expression of Killer-cell Immunoglobulin-like Receptors (KIR + ) and CD45RA (RA + ). These KIR + RA + T cells accumulated with age in the blood of healthy individuals (20-82 years of age, n=50), expressed high levels of the age- related exhaustion marker TIGIT, and were functionally capable of suppressing proliferation of other CD8 + T cells. Moreover, KIR + RA + T cells were found highly activated in older adults suffering from an acute respiratory viral infection (n=36), including coronavirus and influenza-virus infection. Older adults with influenza-A infection showed that the activation status of the KIR + RA + T cells positively correlated with duration of symptoms in (n=15, r =0.6, p =0.03). Together, our data indicate that regulatory KIR + RA + T cells are a previously unrecognized hallmark of aging that may aggravate disease during respiratory viral infections in older adults.