Cross-reactive CD4(+) T cells enhance SARS-CoV-2 immune responses upon infection and vaccination


  • L. Loyal
  • J. Braun
  • L. Henze
  • B. Kruse
  • M. Dingeldey
  • U. Reimer
  • F. Kern
  • T. Schwarz
  • M. Mangold
  • C. Unger
  • F. Dörfler
  • S. Kadler
  • J. Rosowski
  • K. Gürcan
  • Z. Uyar-Aydin
  • M. Frentsch
  • F. Kurth
  • K. Schnatbaum
  • M. Eckey
  • S. Hippenstiel
  • A. Hocke
  • M.A. Müller
  • B. Sawitzki
  • S. Miltenyi
  • F. Paul
  • M.A. Mall
  • H. Wenschuh
  • S. Voigt
  • C. Drosten
  • R. Lauster
  • N. Lachman
  • L.E. Sander
  • V.M. Corman
  • J. Röhmel
  • L. Meyer-Arndt
  • A. Thiel
  • C. Giesecke-Thiel


  • Science


  • Science 374 (6564): eabh1823


  • The functional relevance of pre-existing cross-immunity to SARS-CoV-2 is a subject of intense debate. Here, we show that human endemic coronavirus (HCoV)-reactive and SARS-CoV-2-cross-reactive CD4(+) T cells are ubiquitous but decrease with age. We identified a universal immunodominant coronavirus-specific spike peptide (S816-830) and demonstrate that pre-existing spike- and S816-830-reactive T cells were recruited into immune responses to SARS-CoV-2 infection and their frequency correlated with anti-SARS-CoV-2-S1-IgG antibodies. Spike-cross-reactive T cells were also activated after primary BNT162b2 COVID-19 mRNA vaccination displaying kinetics similar to secondary immune responses. Our results highlight the functional contribution of pre-existing spike-cross-reactive T cells in SARS-CoV-2 infection and vaccination. Cross-reactive immunity may account for the unexpectedly rapid induction of immunity following primary SARS-CoV-2 immunization and the high rate of asymptomatic/mild COVID-19 disease courses.