The TCF1-centered stemness network as the foundation of T cell longevity
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.
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BibTeX
@article{yang2026tcf1centered,
title = {{The TCF1-centered stemness network as the foundation of T cell longevity}},
author = {Qiankun Yang and Annaka M. Saffron and Cornelia M. Weyand and Jörg J. Goronzy},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.2010414},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.2010414},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The TCF1-centered stemness network as the foundation of T cell longevity
AU - Qiankun Yang
AU - Annaka M. Saffron
AU - Cornelia M. Weyand
AU - Jörg J. Goronzy
PY - 2026
DA - 2026/11/09
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.2010414
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.2010414
AB - 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.
SN - 1664-3224
ER -