Dysregulation of homeostatic cytokine receptors drives prolonged T cell activation following acute SARS-CoV-2 infection in humans

Acute viral infections are usually cleared by an efficient anti-pathogen immune response, following which immune homeostasis is restored. Occasionally, such pathogen-induced immune response fails to abate despite clinical recovery, but how this occurs in humans has not been thoroughly investigated. Here, we perform a detailed analysis of T cell homeostasis following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, which reveals persistent activation and dyshomeostasis of CD4⁺ and CD8⁺ T cells for 6-12 months after acute infection. Compared to steady-state and unlike T cell responses following vaccination, interleukin (IL)-2 receptor and IL-7 receptor expression remains altered on both SARS-CoV-2-specific and bystander T cells for 6-12 months after acute infection. These alterations correlate with increased IL-7 and IL-15 serum levels and are reproduced by in vitro stimulation by IL-7 and IL-15, but surprisingly not by IL-2. Collectively, our study demonstrates prolonged T cell dyshomeostasis driven by dysregulated homeostatic cytokine signals following acute viral infection.