Tissue-resident memory CD8 ⁺ T cells in unexposed oropharyngeal lymphoid tissue exhibit specificity for SARS-CoV-2.

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.

Exceptional efforts have been undertaken to shed light into the biology of adaptive immune responses to SARS-CoV-2. T cells occupy a central role in adaptive immunity to mediate helper functions to different arms of the immune system and are fundamental to mediate protection, control, and clearance of most viral infections. Even though many questions remain unsolved, there is a growing literature linking specific T cell characteristics to differential COVID-19 severity and vaccine outcome. In this review, we summarize our current understanding of CD4⁺ and CD8⁺ T cell responses in acute and convalescent COVID-19. Further, we discuss the T cell literature coupled to pre-existing immunity and vaccines and highlight the need to look beyond blood to fully understand how T cells function in the tissue space.