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  3. p16High-expressing immune cells control disease tolerance as a defense and health span-extending strategy

p16High-expressing immune cells control disease tolerance as a defense and health span-extending strategy

  • Immunity. 2026 Mar 26:S1074-7613(26)00083-X. doi: 10.1016/j.immuni.2026.02.013.
Francisco Triana-Martinez 1,  Alessandra Pierantoni 1,  Daisy Graca 2,  Veronica Bergo 3,  Alexander Emelyanov 1,  Alexandre Gallerand 4,  Laurent Grosse 1,  Bogdan B Grigorash 1,  Aikaterini Polyzou 1,  Alexia Castiglione 1,  Shunya Tsuji 5,  Sosuke Nakano 5,  Vesna Brglez 6,  Zakariya Caillot 4,  Pierre Marty 7,  Jean Dellamonica 8,  Stoyan Ivanov 4,  Eiji Hara 5,  Eirini Trompouki 1,  Barbara Seitz-Polski 6,  Dmitry V Bulavin 9
Affiliations

Affiliations

  • 1 Institute for Research on Cancer and Aging of Nice (IRCAN), Université Côte d'Azur, INSERM, CNRS, Nice, France.
  • 2 Laboratoire d'Immunologie, Centre Hospitalier Universitaire de Nice, Nice, France.
  • 3 Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany; International Max Planck Research School for Molecular and Cellular Biology (IMPRS-MCB), Freiburg, Germany.
  • 4 Université Côte d'Azur, CNRS, LP2M, Nice, France.
  • 5 Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
  • 6 Institute for Research on Cancer and Aging of Nice (IRCAN), Université Côte d'Azur, INSERM, CNRS, Nice, France; Laboratoire d'Immunologie, Centre Hospitalier Universitaire de Nice, Nice, France.
  • 7 CHU Hôpital de l'Archet 1, Nice, France.
  • 8 Service de Médecine Intensive Réanimation, CHU, Nice, France; Université Côte d'Azur (UCA), Nice, France.
  • 9 Institute for Research on Cancer and Aging of Nice (IRCAN), Université Côte d'Azur, INSERM, CNRS, Nice, France. Electronic address: dmitry.bulavin@unice.fr.
PMID: 41895292 DOI: 10.1016/j.immuni.2026.02.013
Abstract

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.

Keywords

BNT162b2 mRNA COVID-19 vaccine; Mda5; NNMT; STING; TLR7; adenosine; disease tolerance; healthspan; p16high immune cells.

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