幼児期に樹立された機能的なSARS-CoV-2交差反応性CD4+ T細胞は、年齢とともに減少する。 Functional SARS-CoV-2 cross-reactive CD4+ T cells established in early childhood decline with age
Proceedings of the National Academy of Sciences Published:March 14, 2023
Our results provide evidence that functional pre-existing SARS-CoV-2-reactive memory CD4+ T cells are elicited in early childhood and linked to seroconversion with the seasonal coronavirus OC43 but not many other viral infections. Compared to other viruses, the high OC43 seroprevalence at age two indicates that memory responses to coronaviruses develop at a young age. The distinct age-dependent profiles of the responding T cells suggest that cross-reactive T cells can contribute to the different clinical outcomes of COVID-19 in children and the elderly. The present results provide important advances regarding antigen-specific memory CD4+ T cell development and maturation, which can help guide future vaccine and therapeutic interventions relating to specificity, function, and phenotype of memory T cell responses throughout the human life span.
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.