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

Humbert, Marion; Olofsson, Anna; Wullimann, David; Niessl, Julia; Hodcroft, Emma B; Cai, Curtis; Gao, Yu; Sohlberg, Ebba; Dyrdak, Robert; Mikaeloff, Flora; Neogi, Ujjwal; Albert, Jan; Malmberg, Karl-Johan; Lund-Johansen, Fridtjof; Aleman, Soo; Björkhem-Bergman, Linda; Jenmalm, Maria C; Ljunggren, Hans-Gustaf; Buggert, Marcus and Karlsson, Annika C (2023). Functional SARS-CoV-2 cross-reactive CD4+ T cells established in early childhood decline with age. Proceedings of the National Academy of Sciences of the United States of America - PNAS, 120(12), e2220320120. National Academy of Sciences NAS 10.1073/pnas.2220320120

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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.

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