Resident memory T cells (TRM) positioned within the respiratory tract are probably required to limit SARS-CoV-2 spread and COVID-19. Importantly, TRM are mostly non-recirculating, which reduces the window of opportunity to examine these cells in the blood as they move to the lung parenchyma. Here, we identify circulating virus-specific T cell responses during acute infection with functional, migratory and apoptotic patterns modulated by viral proteins and associated with clinical outcome. Disease severity is associated predominantly with IFNγ and IL-4 responses, increased responses against S peptides and apoptosis, whereas non-hospitalized patients have increased IL-12p70 levels, degranulation in response to N peptides and SARS-CoV-2-specific CCR7+ T cells secreting IL-10. In convalescent patients, lung-TRM are frequently detected even 10 months after initial infection, in which contemporaneous blood does not reflect tissue-resident profiles. Our study highlights a balanced anti-inflammatory antiviral response associated with a better outcome and persisting TRM cells as important for future protection against SARS-CoV-2 infection.

Considering that SARS-CoV-2 interacts with the host at the respiratory tract mucosal interface, T cells strategically placed within these surfaces, namely resident memory T cells, will be essential to limit viral spread and disease. Importantly, these cells are mostly non-recirculating, which reduces the window of opportunity to examine circulating lymphocytes in blood as they home to the lung parenchyma. Here, we demonstrate that viral specific T cells can migrate and establish in the lung as resident memory T cells remaining detectable up to 10 months after initial infection. Moreover, focusing on the acute phase of the infection, we identified virus-specific T cell responses in blood with functional, migratory and apoptotic patterns modulated by viral proteins and associated with clinical outcome. Our study highlights IL-10 secretion by virus-specific T cells associated to a better outcome and the persistence of resident memory T cells as key players for future protection against SARS-CoV-2 infection.

Considering that SARS-CoV-2 interacts with the host at the respiratory tract mucosal interface, T cells strategically placed within these surfaces, namely resident memory T cells, will be essential to limit viral spread and disease. Importantly, these cells are mostly non-recirculating, which reduces the window of opportunity to examine circulating lymphocytes in blood as they home to the lung parenchyma. Here, we demonstrate that viral specific T cells can migrate and establish in the lung as resident memory T cells remaining detectable up to 10 months after initial infection. Moreover, focusing on the acute phase of the infection, we identified virus-specific T cell responses in blood with functional, migratory and apoptotic patterns modulated by viral proteins and associated with clinical outcome. Our study highlights IL-10 secretion by virus-specific T cells associated to a better outcome and the persistence of resident memory T cells as key players for future protection against SARS-CoV-2 infection.