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

Markov, N. S.; Ren, Z.; Senkow, K. J.; Grant, R. A.; Gao, C. A.; Malsin, E. S.; Sichizya, L.; Kihshen, H.; Helmin, K. A.; Jovisic, M.; Arnold, J. M.; Perez-Leonor, X. G.; Abdala-Valencia, H.; Swaminathan, S.; Nwaezeapu, J.; Kang, M.; Rasmussen, L.; Ozer, E. A.; Lorenzo-Redondo, R.; Hultquist, J. F.; Simons, L.; Rios-Guzman, E.; Misharin, A. V.; Wunderink, R. G.; Budinger, G. S.; Singer, B. D.; Morales-Nebreda, L.; The NU SCRIPT Investigators,

doi:10.1101/2023.12.13.571479

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bioRxiv · 10.1101/2023.12.13.571479

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

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Abstract

Pathogen 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-{kappa}B-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-{kappa}B activation against non-structural proteins in patients who go on to experience poor clinical outcomes.

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Markov, N. S., Ren, Z., Senkow, K. J., Grant, R. A., Gao, C. A., Malsin, E. S., Sichizya, L., Kihshen, H., Helmin, K. A., Jovisic, M., Arnold, J. M., Perez-Leonor, X. G., Abdala-Valencia, H., Swaminathan, S., Nwaezeapu, J., Kang, M., Rasmussen, L., Ozer, E. A., Lorenzo-Redondo, R., Hultquist, J. F., Simons, L., Rios-Guzman, E., Misharin, A. V., Wunderink, R. G., Budinger, G. S., Singer, B. D., Morales-Nebreda, L., The NU SCRIPT Investigators,. 2023-12-14. A distinctive evolution of alveolar T cell responses is associated with clinical outcomes in unvaccinated patients with SARS-CoV-2 pneumonia. https://doi.org/10.1101/2023.12.13.571479

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