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

Pieren, Daan K. J.; Smits, Noortje A. M.; Hoeboer, Jeroen; Kandiah, Vinitha; Postel, Rimke J.; Mariman, Rob; van Beek, Josine; van Baarle, Debbie; de Wit, Jelle; Guichelaar, Teun

Severe respiratory viral infectious diseases such as influenza and COVID‐19 especially affect the older population. This is partly ascribed to diminished CD8(+) T‐cell responses 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‐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 aging‐related markers 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 influenza A infection showed that higher activation status of their KIR(+)RA(+) T cells associated 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.