ArticleAging cell2022
Central tolerance is impaired in the middle-aged thymic environment.
Article in Aging cell, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 26 citations in OpenAlex.
- The Thymic Microenvironment Shapes Age-Related Qualitative Changes in the TCR Repertoire.Aging cell · 2026Article
- [Autoimmunity and ageing : How immune ageing shapes disease phenotype, infection risk and treatment safety in rheumatic diseases].Zeitschrift fur Rheumatologie · 2026Review
- GW9508-Induced Activation of GPR40 in Thymic Epithelial Cells: A Therapeutic Strategy to Delay Thymic Aging.Aging cell · 2026Article
- From Development to Aging: Dynamic Roles of the Thymic Medulla in T Cell Biology.Immunological reviews · 2026Review
- Reconstitution of thymopoiesis via implantation of cryopreserved cultured thymus tissue into athymic recipients.American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons · 2026Article
- Targeting Telomerase in Cancer: Vaccine-Based Strategies, Clinical Evidence, and Synergy with Immunotherapy.Diseases (Basel, Switzerland) · 2026Review
- Vitamin D signaling in thymic development and longevity.Frontiers in nutrition · 2026Article
- Cancer cachexia-related monocytic myeloid-derived suppressor cells impair T-cell negative selection and predict immune-related adverse events.Liver research (Beijing, China) · 2025Article
- Single-cell analysis of human thymus and peripheral blood unveils the dynamics of T cell development and aging.Nature aging · 2025Article
- Dendritic Cells: Origin, Classification, Development, Biological Functions, and Therapeutic Potential.MedComm · 2025Review
- Thymic Microenvironment Remodeling in Cancer Cachexia as a Determinant of Checkpoint Inhibitor Efficacy and Toxicity.Journal of cachexia, sarcopenia and muscle · 2025Article
- Intrathymic Regulation of Dendritic Cell Subsets and Their Contributions to Central Tolerance.Immunological reviews · 2025Review
- Enhancing thymic function improves T-cell reconstitution and immune responses in aged mice.PLoS biology · 2025Article
- Paracrine FGF21 dynamically modulates mTOR signaling to regulate thymus function across the lifespan.Nature aging · 2025Article
- Antigen presentation for central tolerance induction.Nature reviews. Immunology · 2025Review
- Mesenchymal stem cells reverse thymus aging by reprogramming the DNA methylation of thymic epithelial cells.Regenerative therapy · 2024Article
- A Chemical Approach to Assess the Impact of Post-translational Modification on MHC Peptide Binding and Effector Cell Engagement.ACS chemical biology · 2024Article
- The Proteostasis of Thymic Stromal Cells in Health and Diseases.The protein journal · 2024Review
- A guide to thymic selection of T cells.Nature reviews. Immunology · 2024Review
- Therapeutic cancer vaccines: advancements, challenges, and prospects.Signal transduction and targeted therapy · 2023Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
One of the earliest hallmarks of immune aging is thymus involution, which not only reduces the number of newly generated and exported T cells, but also alters the composition and organization of the thymus microenvironment. Thymic T-cell export continues into adulthood, yet the impact of thymus involution on the quality of newly generated T-cell clones is not well established. Notably, the number and proportion of medullary thymic epithelial cells (mTECs) and expression of tissue-restricted antigens (TRAs) decline with age, suggesting the involuting thymus may not promote efficient central tolerance. Here, we demonstrate that the middle-aged thymic environment does not support rapid motility of medullary thymocytes, potentially diminishing their ability to scan antigen presenting cells (APCs) that display the diverse self-antigens that induce central tolerance. Consistent with this possibility, thymic slice assays reveal that the middle-aged thymic environment does not support efficient negative selection or regulatory T-cell (Treg) induction of thymocytes responsive to either TRAs or ubiquitous self-antigens. This decline in central tolerance is not universal, but instead impacts lower-avidity self-antigens that are either less abundant or bind to TCRs with moderate affinities. Additionally, the decline in thymic tolerance by middle age is accompanied by both a reduction in mTECs and hematopoietic APC subsets that cooperate to drive central tolerance. Thus, age-associated changes in the thymic environment result in impaired central tolerance against moderate-avidity self-antigens, potentially resulting in export of increasingly autoreactive naive T cells, with a deficit of Treg counterparts by middle age.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.