p16^High immune cells control disease tolerance as a defense and health span-extending strategy

Host survival during infection has traditionally been attributed to pathogen clearance, yet increasing evidence supports a complementary mechanism known as disease tolerance, which limits tissue damage without directly affecting pathogen burden. Here, we identify p16^High immune cells as critical mediators of disease tolerance. We show that the FDA-approved BNT162b2 mRNA COVID-19 vaccine rapidly induces p16^High immune subsets in mice and humans. These cells are required for protection against lipopolysaccharide-induced endotoxin shock, bacterial sepsis, and ionizing irradiation. Mechanistically, Toll-like receptor 7 (TLR7) activation or low-level STING signaling promotes p16^High immune cell induction, reduces adenosine accumulation in part through nicotinamide N-methyltransferase (NNMT)-dependent regulation, and preserves tissue homeostasis. Furthermore, genetic deletion of Ifih1 enhances tonic STING activation and expands p16^High immune subsets, improving resilience to severe inflammation and delaying age-related organ deterioration. Our data highlight the beneficial role of the BNT162b2 mRNA COVID-19 vaccine and Ifih1attenuation in inducing disease tolerance through protective p16^High immune subsets.