p16High 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 p16High immune cells as critical mediators of disease tolerance. We show that the FDA-approved BNT162b2 mRNA COVID-19 vaccine rapidly induces p16High 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 p16High 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 p16High 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 p16High immune subsets.