Profound dysregulation of T cell homeostasisand function in patients with severe COVID-19.

Background Coronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and shows a broad clinical presentation ranging from asymptomatic infection to fatal disease. A very prominentfeature associated with severe COVID-19 is T cell lymphopenia. However, homeostatic and functional properties of T cells are ill-defined in COVID-19. Methods We prospectively enrolled individuals with mild and severe COVID-19 into our multicenter cohort and performed a cross-sectional analysis of phenotypic and functional characteristics of T cells using 40-parameter mass cytometry, flow cytometry, targeted proteomics, and functional assays. Results Compared tomild disease, we observed strong perturbations of peripheral T cell homeostasis and function in severe COVID-19. Individuals with severe COVID-19 showed T cell lymphopenia and redistribution of T cell populations, including loss of naiveT cells, skewing toward CD4+ T follicular helper cells and cytotoxic CD4+ T cells,and expansion of activated and exhausted T cells. Extensive T cell apoptosis was particularly evident with severe disease and T cell lymphopenia,which in turn was accompanied by impaired T cell responses to several common viral antigens. Patients with severe disease showed elevated interleukin-7 and increased T cell proliferation. Furthermore, patients sampled at late time points after symptom onset had higher T cell counts and improved antiviral T cell responses. Conclusion Our study suggests that severe COVID-19 is characterized by extensiveT cell dysfunction and T cell apoptosis, which is associated with signs of homeostatic T cell proliferation and T cell recovery.