A distinctive evolution of alveolar T cell responses is associated with clinical outcomes in unvaccinated patients with SARS-CoV-2 pneumonia

• DOI: 10.1101/2023.12.13.571479
• Publication Date: 2023-12-15T02:50:18Z
• Authors: Nikolay S. Markov; Ziyou Ren; Karolina J. Senkow; Rogan A. Grant; Catherine A. Gao; Elizabeth S. Malsin; Lango Sichizya; Hermon Kihshen; Kathryn A. Helmin; Milica Jovisic; Jason M. Arnold; Xóchitl G. Pérez-...; Hiam Abdala-Valencia; Suchitra Swaminathan; Julu Nwaezeapu; Mengjia Kang; Luke Rasmussen; Egon A. Ozer; Ramon Lorenzo-Red...; Judd F. Hultquist; Lacy M. Simons; Estefany Rios-Guzman; Alexander V. Mish...; Richard G. Wunderink; G.R. Scott Budinger; Benjamin D. Singer; Luisa Morales-Neb...
• Keywords: Male; Adult; SARS-CoV-2; T-Lymphocytes; NF-kappa B; COVID-19; Middle Aged; Article; Pulmonary Alveoli; T-Lymphocyte Subsets; Spike Glycoprotein, Coronavirus; Humans; Female; Interferons; Bronchoalveolar Lavage Fluid; Aged; Signal Transduction

AbstractPathogen clearance and resolution of inflammation in patients with pneumonia require an effective local T cell response. Nevertheless, local T cell activation may drive lung injury, particularly during prolonged episodes of respiratory failure characteristic of severe SARS-CoV-2 pneumonia. While T cell responses in the peripheral blood are well described, the evolution of T cell phenotypes and molecular signatures in the distal lung of patients with severe pneumonia caused by SARS-CoV-2 or other pathogens is understudied. Accordingly, we serially obtained 432 bronchoalveolar lavage fluid samples from 273 patients with severe pneumonia and respiratory failure, including 74 unvaccinated patients with COVID-19, and performed flow cytometry, transcriptional, and T cell receptor profiling on sorted CD8+and CD4+T cell subsets. In patients with COVID-19 but not pneumonia secondary to other pathogens, we found that early and persistent enrichment in CD8+and CD4+T cell subsets correlated with survival to hospital discharge. Activation of interferon signaling pathways early after intubation for COVID-19 was associated with favorable outcomes, while activation of NF-κB-driven programs late in disease was associated with poor outcomes. Patients with SARS-CoV-2 pneumonia whose alveolar T cells preferentially targeted the Spike and Nucleocapsid proteins tended to experience more favorable outcomes than patients whose T cells predominantly targeted the ORF1ab polyprotein complex. These results suggest that in patients with severe SARS-CoV-2 pneumonia, alveolar T cell interferon responses targeting structural SARS-CoV-2 proteins characterize patients who recover, yet these responses progress to NF-κB activation against non-structural proteins in patients who go on to experience poor clinical outcomes.