Regulatory KIR+RA+ T cells accumulate with age and are highly activated during viral respiratory disease

Severe respiratory viral infectious diseases such as influenza and COVID- 19 espe-cially affect the older population. This is partly ascribed to diminished CD8+ T- cell re-sponses a result of aging. The 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-l ike 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 aging- related mark-ers of T- cell regulation, and were functionally capable of suppressing proliferation of other CD8+ T cells. Moreover, KIR+RA+ T cells were a major T- cell subset becoming activated in older adults suffering from an acute respiratory viral infection (n = 36), including coronavirus and influenza virus infection. In addition, older adults with influ-enza A infection showed that higher activation status of their KIR+RA+ T cells associ-ated with longer duration of respiratory symptoms. Together, our data indicate that KIR+RA+ T cells are a unique human T- cell subset with regulatory properties that may explain susceptibility to viral respiratory disease at old age. Overall design: KIR+RA+, NKG2A+RA+, TNAIVE, and TEMRA cell subsets were sorted from healthy donor PBMCs (n = 6) and their gene expression profiles were analyzed by Next-Generation Sequencing using the Illumina Nextseq