Objectives: Our previous study in hospitalised patients infected with avian A(H7N9) influenza virus identified CD84 amongst several genes associated with recovery. Yet, the correlation between CD84 and respiratory viral infection outcomes is far from established. We aimed to define CD84 dynamics in patient cohorts of respiratory disease and immune cell populations in influenza virus-infected mice.

Methods: Expression dynamics of CD84 and association with previously identified correlates of severe and fatal respiratory disease outcomes, OLAH and IL18R1, were analysed in A(H7N9) and COVID-19 patient cohorts across disease severities. Using mouse models of influenza virus infection, CD84 expression on immune cell subsets was analysed over the course of infection.

Results: Elevated CD84 levels in recovered A(H7N9) patients were accompanied by increased expression of genes for CD84-associated adaptor proteins and other SLAM receptor family members. In these patients, high CD84 expression persisted until discharge, while remaining low throughout the disease in patients that succumbed. We found inverse correlations between CD84 with OLAH and IL18R1 levels in our A(H7N9) cohort, and in hospitalised COVID-19 patients across respiratory disease severities. In influenza virus-infected mice, CD84 was upregulated on a broad range of immune cell populations, particularly on activated and influenza virus-specific T-cell populations and correlated with less disease severity.

Conclusion: Our findings revealed the link between high CD84 expression in humans and recovery from respiratory viral infections. In mice, CD84 expression increased across a broad range of immune cell populations, with CD84 expression on activated T-cell populations correlating with less severe disease.