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

Abstract

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.