SARS-CoV-2-specific T cells associate with reduced lung function and inflammation in pulmonary post-acute sequalae of SARS-CoV-2
Authors: Littlefield Katherine M. , Watson Renée O. , Schneider Jennifer M. , Neff Charles P. , Yamada Eiko , Zhang Min , Campbell Thomas B. , Falta Michael T. , Jolley Sarah E. , Fontenot Andrew P. , Palmer Brent E. 
Published: February 2022

AbstractAs of January 2022, at least 60 million individuals are estimated to develop post-acute sequelae of SARS-CoV-2 (PASC) after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While elevated levels of SARS-CoV-2-specific T cells have been observed in non-specific PASC, little is known about their impact on pulmonary function which is compromised in the majority of these individuals. This study compares frequencies of SARS-CoV-2-specific T cells and inflammatory markers with lung function in participants with pulmonary PASC and resolved COVID-19 (RC). Compared to RC, participants with respiratory PASC had up to 34-fold higher frequencies of IFN-γ- and TNF-α-producing SARS-CoV-2-specific CD4+ and CD8+ T cells in peripheral blood and elevated levels of plasma CRP and IL-6. Importantly, in PASC participants the frequency of TNF-α-producing SARS-CoV-2-specific CD4+ and CD8+ T cells, which exhibited the highest levels of Ki67 indicating they were activity dividing, correlated positively with plasma IL-6 and negatively with measures of lung function, including forced expiratory volume in one second (FEV1), while increased frequencies of IFN-γ-producing SARS-CoV-2-specific T cells associated with prolonged dyspnea. Statistical analyses stratified by age, number of comorbidities and hospitalization status demonstrated that none of these factors affect differences in the frequency of SARS-CoV-2 T cells and plasma IL-6 levels measured between PASC and RC cohorts. Taken together, these findings demonstrate elevated frequencies of SARS-CoV-2-specific T cells in individuals with pulmonary PASC are associated with increased systemic inflammation and decreased lung function, suggesting that SARS-CoV-2-specific T cells contribute to lingering pulmonary symptoms. These findings also provide mechanistic insight on the pathophysiology of PASC that can inform development of potential treatments to reduce symptom burden.Author SummaryLong COVID-19 or post-acute sequelae of SARS-CoV-2 (PASC) impacts 20-30% of those infected with SARS-CoV-2 and is characterized by COVID-19 symptoms exceeding 4 weeks from symptom onset. While those with PASC experience a wide variety of persistent symptoms including shortness of breath, cough, chest pain, irregular heartbeat, brain fog, fatigue, and intermittent fever, lung-related conditions are the most common. Although, infection with SARS-CoV-2 is clearly the inciting factor for PASC, the mechanisms responsible for long-term lung dysfunction are unclear and current treatments are ineffective at resolving pulmonary symptoms. Generalized PASC has been associated with SARS-CoV-2-specific T cells, a component of adaptive immunity, suggesting that residual virus may persist. Here, we investigated the frequency and function of virus-specific T cells in the blood of individuals with pulmonary PASC and correlated their presence with systemic inflammation and lung function. Our findings demonstrated that T cells specific for SARS-CoV-2 are elevated in the blood of those with pulmonary PASC and are associated with increased IL-6, a cytokine strongly associated with COVID-19 severity, and decreased lung function. These findings provide mechanistic insight into the pathophysiology of pulmonary PASC needed for the development of new treatments to improve quality of life for those affected.