Year: 2026
Type: article
Abstract: Adaptive immunity depends on the extraordinary longevity of the T-cell compartment, yet the mechanisms that sustain immune competence across decades remain incompletely understood. Traditional models emphasize homeostatic proliferation and cellular replacement as the basis of T-cell maintenance. Here, we propose an alternative framework in which long-term immune resilience depends primarily on preservation of stemness through cellular quiescence. Evidence from human aging studies indicates that naïve and stem-like memory T cells achieve exceptional longevity by limiting rather than maximizing turnover. Aging is therefore best understood as a progressive loss of stem-like cellular states, characterized by erosion of a TCF1-centered regulatory network that integrates FOXO1-dependent quiescence, BACH2-mediated restraint of differentiation, Wnt-dependent stemness reprogramming, and lysosomal-metabolic fitness. Exemplified by this model, intrinsic differences in the ability to maintain this network may account for the unequal aging of CD4 and CD8 T cells. Preserving T-cell stemness may represent a central goal of immune rejuvenation strategies.
Source: Frontiers in Immunology
Institution: Mayo Clinic
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
Funder: National Institutes of Health
OpenAlex ID: W7225645286