In this preprint by Braun et al., CD4+ T cell responses to SARS-CoV-2 infection were characterized in 18 patients with COVID-19 and 68 seronegative healthy donors (HDs). Peripheral blood mononuclear cells from patients and HDs were stimulated with peptide pools derived from the SARS-CoV-2 spike (S) protein. S protein-specific CD4+ T cells were found in most of the patients with COVID-19, but also in a portion of HDs. CD4+ T cells from patients with COVID-19 had a phenotype of recent activation in contrast to those from HDs. The authors suggest that S protein-specific T cells in HDs may be cross-reactive clones developed following a previous exposure to human endemic coronaviruses that cause common cold. Further validation with larger cohorts and more functional assessment, including the use of control peptides, are needed to establish whether these T cells are truly reactive to SARS-CoV-2.