The emergence of SARS-CoV-2 in late 2019 and its subsequent global spread has led to millions of infections and substantial morbidity and mortality (1). Coronavirus disease 2019 (COVID-19), the clinical disease caused by SARS-CoV-2 infection, can range from mild self-limiting disease to acute respiratory distress syndrome and death (2). The mechanisms underlying the spectrum of COVID-19 disease severity states, and the nature of protective immunity against COVID-19 currently remains unclear.
Studies dissecting the human immune response against SARS-CoV-2 have begun to characterize SARS-CoV-2 antigen-specific T cell responses (3–8), and multiple studies have described marked activation of T cell subsets in acute COVID-19 patients (9–13). Surprisingly, antigen-specific T cell studies performed with five different cohorts reported that 20-50% of people who had not been exposed to SARS-CoV-2 had significant T cell reactivity directed against peptides corresponding to SARS-CoV-2 sequences (3–7). The studies were from geographically diverse cohorts (USA, Netherlands, Germany, Singapore, and UK), and the general pattern observed was that the T cell reactivity found in unexposed individuals was predominantly mediated by CD4+ T cells. It was speculated that this phenomenon might be due to preexisting memory responses against human “common cold” coronaviruses (HCoVs), such as HCoV-OC43, HCoV-HKU1, HCoV-NL63, or HCoV-229E. These HCoVs share partial sequence homology with SARS-CoV-2, are widely circulating in the general population, and are typically responsible for mild respiratory symptoms (14–16). However, the hypothesis of crossreactive immunity between SARS-CoV-2 and common cold HCoVs still awaits experimental trials. This potential preexisting cross-reactive T cell immunity to SARS-CoV-2 has broad implications, as it could explain aspects of differential COVID-19 clinical outcomes, influence epidemiological models of herd immunity (17, 18), or affect the performance of COVID-19 candidate vaccines.