Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the rapidly unfolding coronavirus disease 2019 (COVID-19) pandemic1^,2. Clinical manifestations of COVID-19 vary, ranging from asymptomatic infection to respiratory failure. The mechanisms that determine such variable outcomes remain unresolved. Here we investigated CD4⁺ T cells that are reactive against the spike glycoprotein of SARS-CoV-2 in the peripheral blood of patients with COVID-19 and SARS-CoV-2-unexposed healthy donors. We detected spike-reactive CD4⁺ T cells not only in 83% of patients with COVID-19 but also in 35% of healthy donors. Spike-reactive CD4⁺ T cells in healthy donors were primarily active against C-terminal epitopes in the spike protein, which show a higher homology to spike glycoproteins of human endemic coronaviruses, compared with N-terminal epitopes. Spike-protein-reactive T cell lines generated from SARS-CoV-2-naive healthy donors responded similarly to the C-terminal region of the spike proteins of the human endemic coronaviruses 229E and OC43, as well as that of SARS-CoV-2. These results indicate that spike-protein cross-reactive T cells are present, which were probably generated during previous encounters with endemic coronaviruses. The effect of pre-existing SARS-CoV-2 cross-reactive T cells on clinical outcomes remains to be determined in larger cohorts. However, the presence of spike-protein cross-reactive T cells in a considerable fraction of the general population may affect the dynamics of the current pandemic, and has important implications for the design and analysis of upcoming trials investigating COVID-19 vaccines.

The COVID-19 pandemic poses a threat to public health and the global economy as the number of cases and COVID-19-related deaths increases worldwide. COVID-19 is routinely diagnosed by the detection of SARS-CoV-2 RNA in nasopharyngeal swabs using PCR, the detection of which is reliable during the acute phase of COVID-19. However, the limited availability of tests and the preferential testing of patients with symptoms has probably led to a marked underestimation of the infection burden and overestimation of fatality rates. Serological analysis of SARS-CoV-2-induced humoral immunity could reveal asymptomatic infections, but it is not yet widely applied and is complicated by the fact that coronavirus-induced antibody responses are variable and short-lived coronavirus-induced cellular immunity is predicted to be more sustained, but remains poorly characterized. However, several T cell epitopes in the structural proteins of coronaviruses have been predicted or identified. Identified S-reactive CD4⁺ T cells by flow cytometry according to their expression of CD40L and 4-1BB after in vitro stimulation with S peptides. To this end, we designed two peptide pools (15 amino acids with 11 amino acid overlaps) that spanned the entire S protein and that contained different amounts of putative MHC-II epitopes based on epitopes identified in SARS-CoV. For antigen-specific stimulation, peripheral blood mononuclear cells from patients and HDs were stimulated for 16 h with S-I and S-II peptide pools Notably, S-II-reactive CD4+ T cells—although at slightly lower frequencies compared with patients with COVID-19—could also be detected in 24 out of 68 HDs (35%), who are hereafter referred to as reactive healthy donors S-I-reactive CD4+ T cells could be detected in only 6 out of the 24 RHDs, that is, in 5.8% of all HDs

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