The aged adaptive immune system is characterized by progressive dysfunction as well as increased autoimmunity. This decline is responsible for elevated susceptibility to infection and cancer, as well as decreased vaccination efficacy. Recent evidence indicates that CD4+ T cell–intrinsic alteratins contribute to chronic inflammation and are sufficient to accelerate an organism-wide aging phenotype, supporting the idea that T cell aging plays a major role in body-wide deterioration. In this Review, we propose ten molecular hallmarks to represent common denominators of T cell aging. These hallmarks are grouped into four primary hallmarks (thymic involution, mitochondrial dysfunction, genetic and epigenetic alterations, and loss of proteostasis) and four secondary hallmarks (reduction of the TCR repertoire, naive–memory imbalance, T cell senescence, and lack of effector plasticity), and together they explain the manifestation of the two integrative hallmarks (immunodeficiency and inflammaging). A major challenge now is weighing the relative impact of these hallmarks on T cell aging and understanding their interconnections, with the final goal of defining molecular targets for interventions in the aging process.
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M.M. is supported by the Miguel Servet Program (CP 19/014, Fundación de Investigación del Hospital 12 de Octubre; the Fondo de Investigación Sanitaria del Instituto de Salud Carlos III (PI19/855), the European Regional Development Fund (ERDF), and the European Commission through H2020-EU.1.1 and European Research Council grant ERC-2016-StG 715322-EndoMitTalk. G.K. is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR) — Projets blancs; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Association ‘Ruban Rose’; Cancéropôle Ile-de-France; Chancelerie des universités de Paris (Legs Poix), Fondation pour la Recherche Médicale (FRM); a donation by Elior; European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR); Gustave Roussy Odyssea, the European Union Horizon 2020 Project Oncobiome; Fondation Carrefour; High-end Foreign Expert Program in China (GDW20171100085), Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology (ANR-18-IDEX-0001); the RHU Torino Lumière; the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and the SIRIC Cancer Research and Personalized Medicine (CARPEM). This study contributes to the IdEx Université de Paris ANR-18-IDEX-0001.
G.K. is the scientific cofounder of three biotech companies dealing with age-related diseases: everImmune, Samsara Therapeutics, and Therast Bio.
Peer review information Nature Immunology thanks Rene van Lier and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Jamie D. K. Wilson was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
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Mittelbrunn, M., Kroemer, G. Hallmarks of T cell aging. Nat Immunol 22, 687–698 (2021). https://doi.org/10.1038/s41590-021-00927-z
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