Functional SARS-CoV-2 cross-reactive CD4+ T cells established in early childhood decline with age

Proc Natl Acad Sci U S A. 2023 Mar 21;120(12):e2220320120. doi: 10.1073/pnas.2220320120. Epub 2023 Mar 14.


Pre-existing SARS-CoV-2-reactive T cells have been identified in SARS-CoV-2-unexposed individuals, potentially modulating COVID-19 and vaccination outcomes. Here, we provide evidence that functional cross-reactive memory CD4+ T cell immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is established in early childhood, mirroring early seroconversion with seasonal human coronavirus OC43. Humoral and cellular immune responses against OC43 and SARS-CoV-2 were assessed in SARS-CoV-2-unexposed children (paired samples at age two and six) and adults (age 26 to 83). Pre-existing SARS-CoV-2-reactive CD4+ T cell responses targeting spike, nucleocapsid, and membrane were closely linked to the frequency of OC43-specific memory CD4+ T cells in childhood. The functional quality of the cross-reactive memory CD4+ T cell responses targeting SARS-CoV-2 spike, but not nucleocapsid, paralleled OC43-specific T cell responses. OC43-specific antibodies were prevalent already at age two. However, they did not increase further with age, contrasting with the antibody magnitudes against HKU1 (β-coronavirus), 229E and NL63 (α-coronaviruses), rhinovirus, Epstein-Barr virus (EBV), and influenza virus, which increased after age two. The quality of the memory CD4+ T cell responses peaked at age six and subsequently declined with age, with diminished expression of interferon (IFN)-γ, interleukin (IL)-2, tumor necrosis factor (TNF), and CD38 in late adulthood. Age-dependent qualitative differences in the pre-existing SARS-CoV-2-reactive T cell responses may reflect the ability of the host to control coronavirus infections and respond to vaccination.

Keywords: SARS-CoV-2; T cell specificity; age groups; cross-protection; human coronavirus OC43.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Viral
  • CD4-Positive T-Lymphocytes
  • COVID-19*
  • Child
  • Child, Preschool
  • Cross Reactions
  • Epstein-Barr Virus Infections*
  • Herpesvirus 4, Human
  • Humans
  • Middle Aged
  • SARS-CoV-2
  • Spike Glycoprotein, Coronavirus
  • T-Lymphocytes


  • Spike Glycoprotein, Coronavirus
  • Antibodies, Viral
  • spike protein, SARS-CoV-2