Functional SARS-CoV-2 cross-reactive CD4 <sup>+</sup> T cells established in early childhood decline with age
Marion Humbert, Anna Olofsson, David Wullimann, Julia Niessl, Emma B. Hodcroft, Curtis Cai, Yu Gao, Ebba Sohlberg, Robert Dyrdak, Flora Mikaeloff, Ujjwal Neogi, Jan Albert, Karl‐Johan Malmberg, Fridtjof Lund‐Johansen, Soo Aleman, Linda Björkhem‐Bergman, Maria C. Jenmalm, Hans‐Gustaf Ljunggren, Marcus Buggert, Annika C. Karlsson
Abstract
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.