The immune system responds to SARS-CoV-2 differently depending on age. Children more often experience mild or asymptomatic infections, while older individuals frequently face severe disease.
Previous studies showed that type I interferon (IFN) pathways are more strongly activated in epithelial and innate immune cells of children, a key factor in early antiviral defense. However, viral load and clearance rates were found to be similar across ages.
For long-term infection control, T cells and antibodies are essential. T cells aid in viral clearance, while neutralizing antibodies reduce reinfection risk. In most children, adaptive immune responses form without systemic inflammation. In contrast, elderly patients with severe COVID-19 exhibit immune cell dysfunction — including excessive cytotoxic T-cell activity and impaired myeloid cell function, highlighting qualitative, age-dependent differences in immune responses, though the molecular basis was previously unknown.
As part of the RECAST study, researchers performed a comprehensive molecular analysis of immune cells from children and adults infected early in the pandemic, as well as uninfected donors. They identified a continuous age-related shift in IFN-I signaling: with age, monocytes, T cells, and B cells transition from STAT1-driven to STAT3-driven signaling. This remodeling is linked to altered inflammatory gene expression in immune cells and contributes to systemic inflammation in older adults.
Although plasmacytoid dendritic cell numbers decline with age, IFN-α production levels remain stable in older individuals, suggesting that age-related differences stem not from reduced IFN production but from altered downstream signaling.
IFN-I can activate either STAT1/STAT2 or STAT3. The latter can suppress canonical IFN signaling, tipping the balance toward proinflammatory responses.
In children, IFN-stimulated gene (ISG) activation is accompanied by high levels of HLA-DR — an MHC class II molecule — on monocytes, as well as formation of follicular T and B cells, supporting IgA antibody production. Aging, by contrast, leads to reduced HLA-DR expression, expansion of peripheral T helper cells, and emergence of atypical B cells, resulting in a less specific and more inflammatory immune response, dominated by IgG antibodies and complement activation.
STAT3 hyperactivation is associated with transcriptional reprogramming in monocytes, CD4 T cells, and B cells during aging. STAT3 can suppress MHC II expression, consistent with low HLA-DR levels on monocytes in older adults. Monocytes from older adults also showed enriched transcription of CXCL8, CXCL2, and S100A8/A9/12 — all known STAT3 targets.
STAT3 promotes the formation of atypical B cells, which are stimulated by expanded peripheral T helper cells. These processes are linked to severe COVID-19.
In older adults, antibody production shifts toward IgG, which enhances classical complement activation. In contrast, children predominantly produce IgA, which is key for mucosal immunity, matching earlier findings showing that complement activation directly contributes to T cell–driven immunopathology in elderly COVID-19 patients.
Conclusion
With aging, type I interferon signaling is rewired. Children predominantly mount STAT1/STAT2-dependent protective responses, while adults rely increasingly on STAT3-mediated inflammatory processes. These changes are especially pronounced after age 55 and are associated with a higher risk of severe COVID-19. Recognizing this shift is vital for future vaccine design and therapeutic strategies.
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Reference
Rewired type I IFN signaling is linked to age-dependent differences in COVID-19
