The clinical manifestations of COVID-19 vary from asymptomatic infection to respiratory failure. Severe disease courses are primarily associated with advanced age, immune dysfunctions, and comorbidities. Initially, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was thought to encounter an immunologically unprotected population. However, SARS-CoV-2 has significant homologies with endemic seasonal cold coronaviruses (HCoVs), and recent HCoV infection is associated with a less severe course of COVID-19, suggesting a protective role of cross-reactive immunity.

The preexistence of SARS-CoV-2–cross-reactive CD4⁺ T cells in unexposed individuals has been repeatedly demonstrated, but their contribution to host responses is an active area of investigation. Here, we investigated the functional role of preexisting SARS-CoV-2–cross-reactive and HCoV-reactive CD4⁺ T cells with high resolution.

We demonstrate broad CD4⁺ T cell cross-reactivity in unexposed individuals, with the spike glycoprotein serving as one of the immunodominant targets. Although the N-terminal part of spike (covered by the S-I peptide pool) did not elicit cross-reactive T cell responses, the more HCoV-homologous C-terminal section (covered by the S-II peptide pool) induced T cell responses in unexposed donors. We identified a universal immunodominant coronavirus peptide located within the fusion peptide domain of spike (S816-830) recognized by CD4⁺ T cells in 20% of unexposed individuals, 50 to 60% of SARS-CoV-2 convalescents, and 97% of BNT162b2-vaccinated individuals. S816-830– and spike–cross-reactive T cells were recruited in immune responses to SARS-CoV-2 infection and BNT162b2 COVID-19 mRNA vaccination. S816-830-reactive T cells initially contributed up to 100% of the S-II–reactive CD4⁺ T cells but their proportion decreased during the course of the S-II–specific immune response. Upon primary vaccination, cross-reactive cellular and humoral immunity exhibited kinetics typical for secondary immune responses. The frequencies of preexisting cross-reactive T cells correlated positively with functional avidity of the T cell receptor, as well as with the induction and stabilization of anti–SARS-CoV-2-S1-IgG and neutralizing antibodies. Although HCoV-responsive T cells are ubiquitous, their frequencies and the frequencies of SARS-CoV-2–cross-reactive CD4⁺ T cells decreased with age, consistent with an increased vulnerability of the elderly to severe COVID-19 disease.

Preexisting cross-reactive CD4⁺ T cells enhance immune responses in SARS-CoV-2 infection and BNT162b2 vaccination. Because these cells are greatly diminished in the elderly, our results suggest that their decrease may contribute to the increased susceptibility of this population to severe COVID-19. Preexisting cross-reactive immunity may be responsible for the unexpectedly rapid induction of protective immunity after primary SARS-CoV-2 immunization and the high rate of asymptomatic and mild COVID-19 disease courses.

(A) Preexisting SARS-CoV-2 S-II– and spike (S)816-830–cross-reactive T cells show booster response characteristics upon SARS-CoV-2 infection and vaccination and their abundance correlates with higher protective anti–SARS-CoV-2 S1-IgG titers and higher functional T cell avidity. (B) The frequency of HCoV-reactive and SARS-CoV-2–cross-reactive T cells decreases with age.