Presence of SARS-CoV-2-reactive T cells in COVID-19 patients and healthy donors

Summary Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a rapidly unfolding pandemic, overwhelming health care systems worldwide 1 . Clinical manifestations of Coronavirus-disease 2019 (COVID-19) vary broadly, ranging from asymptomatic infection to acute respiratory failure and death 2 , yet the underlying mechanisms for this high variability are still unknown. Similarly, the role of host immune responses in viral clearance of COVID-19 remains unresolved. For SARS-CoV (2002/03), however, it has been reported that CD4 + T cell responses correlated with positive outcomes 3,4 , whereas T cell immune responses to SARS-CoV-2 have not yet been characterized. Here, we describe an assay that allows direct detection and characterization of SARS-CoV-2 spike glycoprotein (S)-reactive CD4 + T cells in peripheral blood. We demonstrate the presence of S-reactive CD4 + T cells in 83% of COVID-19 patients, as well as in 34% of SARS-CoV-2 seronegative healthy donors (HD), albeit at lower frequencies. Strikingly, S-reactive CD4 + T cells in COVID-19 patients equally targeted N-terminal and C-terminal epitopes of S whereas in HD S-reactive CD4 + T cells reacted almost exclusively to the C-terminal epitopes that are a) characterized by higher homology with spike glycoprotein of human endemic “common cold” coronaviruses (hCoVs), and b) contains the S2 subunit of S with the cytoplasmic peptide (CP), the fusion peptide (FP), and the transmembrane domain (TM) but not the receptor-binding domain (RBD). In contrast to S-reactive CD4 + T cells in HD, S-reactive CD4 + T cells from COVID-19 patients co-expressed CD38 and HLA-DR, indivative of their recent in vivo activation. Our study is the first to directly measure SARS-CoV-2-reactive T cell responses providing critical tools for large scale testing and characterization of potential cross-reactive cellular immunity to SARS-CoV-2. The presence of pre-existing SARS-CoV-2-reactive T cells in a subset of SARS-CoV-2 naïve HD is of high interest but larger scale prospective cohort studies are needed to assess whether their presence is a correlate of protection or pathology for COVID-19. Results of such studies will be key for a mechanistic understanding of the SARS-CoV-2 pandemic, adaptation of containment methods and to support vaccine development.