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

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.

Age and co-morbidities as independent risk factors of infections leading to hospital admission in the last year of life among the elderly: A retrospective registry-based study

“…Previous studies have shown that elderly persons are generally more susceptible to infections and often have poorer outcomes of infections compared to younger individuals ( 1 , 2 , 17 ). Interestingly, our results also show that chronological age is an independent risk factor, also when adjustment was made for co-morbidities.…”

Distinct T cell polyfunctional profile in SARS-CoV-2 seronegative children associated with endemic human coronavirus cross-reactivity

“… 52 , 54 While cross reactive humoral responses have been shown not to underly this protection, 55 studies have reported pre-existing T cell responses to endemic HCoVs with cross-reactivity to SARS-CoV-2 in unexposed adults 50 , 56 , 57 , 58 , 59 , 60 , 61 and children. 22 , 24 , 62 , 63 These cellular responses were targeted mainly toward the S2 subunit which is highly conserved among coronaviruses. 22 , 25 In our study, we showed a positive correlation between the frequency of SARS-CoV-2 CD4 + T cells and the magnitude of HKU1 spike-specific IgG in SARS-CoV-2 seronegative children.…”

“… 7 Several age-associated factors have been proposed to play a role in the reduction of severity to SARS-CoV-2 infection in children, 2 , 8 including limited comorbidities, 9 , 10 , 11 differences in the expression of SARS-CoV-2 viral entry factors, 12 , 13 , 14 robust innate immune responses, 15 , 16 , 17 , 18 humoral and cellular immunity 19 , 20 , 21 and pre-existing immunity against common cold circulating endemic HCoVs. 22 , 23 , 24 , 25 , 26 Endemic HCoVs account for 15 to 30% of respiratory infections reported annually in children. 27 , 28 These HCoVs belong to the alpha-coronavirus subfamily (HCoV-229E and HCoV-NL63) and the beta-coronavirus subfamily (HCoV-OC43 and HCoV-HKU1), are generally considered to have seasonal infection peaks during the winter season and are responsible for high rates of infection among children.…”

Differential Adaptive Immune Responses Following SARS-CoV-2 Infection in Children Compared to Adults

“…As mentioned above, memory T cells generated following HCoV infections are able to cross-react with SARS-CoV-2 antigens, as demonstrated using pre-pandemic samples, in both adults and children. 39–41 This cross-reactivity is established very early in life. 39 However, despite numerous HCoV exposures, Humbert et al showed the capacity of T cells to cross-react declines with age, as does the capacity of CD4 + T cells to respond to HCoV.…”

“…39–41 This cross-reactivity is established very early in life. 39 However, despite numerous HCoV exposures, Humbert et al showed the capacity of T cells to cross-react declines with age, as does the capacity of CD4 + T cells to respond to HCoV. 39,41 In line with this, we report that the increased level of T-cell memory observed in adults is unique to SARS-CoV-2 and is not seen when evaluating responses to other seasonal HCoV, as demonstrated by their lower level of response to HCoV-HKU1 and HCoV-OC43.…”