T-cell Longevity Collaborative

Established in 2026, the T-cell Longevity Collaborative aims to define the mechanisms of cancer-free T cell aging. CD8 T cells are unique among somatic cells for their ability to undergo rapid, tightly regulated clonal expansion, sometimes dividing every six hours during a robust immune response. This rapid growth equips the body with the cells needed to control an invading pathogen. However, under sustained antigen exposure, T cells undergo a developmental shift that limits their ability to proliferate in the future. In contrast, brief antigen encounters followed by periods of rest allow memory T cells to retain their proliferative potential repeatedly. Until recently, it was not known whether T cells could maintain this capacity over the full lifespan of the host when challenged repeatedly by a pathogen that is acutely resolved. This question carries major implications for vaccine design and T cell–based immunotherapies and reflects a core principle of cell biology: how cells preserve replicative fidelity while avoiding senescence.

T cell–based immunotherapies have introduced the prospect of durable, self-renewing “living drugs” capable of providing long-term protection against disease relapse. This type of sustained immunity is especially significant for pediatric patients, for whom early‑life cancers pose lifelong risks. Yet the development of engineered T cells raises fundamental questions: Do these cells age, and does repeated activation increase susceptibility to malignant transformation? Recent work has shown that organismal aging is linked to chronological, locus-specific epigenetic modifications calibrated to species lifespan. Building on this insight, this group leveraged a multi-lifetime murine model to identify epigenetic metrics that distinguish T cell age from the age of the host.

Studies revealed that memory T cells encode a distinct epigenetic clock tied to their proliferative history, characterized by progressive DNA methylation at genes governing cell cycle entry. Notably, long lived mouse and human memory T cells do not acquire epigenetic programs associated with T cell leukemogenesis. These findings, drawn from complementary murine and human aging cohorts, highlight candidate genes and pathways that may lie behind the cancer resistant phenotype of aged T cells. Together, they suggest that memory T cells can live well-beyond typical organismal lifespan and can serve as a blueprint for engineering T cell therapies with sustained proliferative capacity while maintaining oncologic safety. To advance this effort, this group assembled the T-cell Longevity Collaborative with expertise in T cell immunity, the epi-mutational theory of aging, and metabolomics to define the mechanisms that enable T cells to remain functional across unprecedented cellular timespans.

The T-cell Longevity Collaborative is focused on three main projects. The first project, led by Collaborative members Ben Youngblood, PhD and David Masopust, PhD, will investigate T cell senescence and epigenetic aging in young and aged hosts. Their labs aim to determine if host age delineates senescent versus functional T cell aging, to define core epigenetic programs that enable functional persistence of iteratively stimulated T cells (ISTCs), to determine if epigenetic programs restrict the repertoire of ISTCs, and to discover if leukemia-associated “epi-mutations” transform long-lived mature memory T cells into cancer.

The second project led by Xiao Dong, PhD, and Jan Vijg, PhD, will examine how somatic mutations and epigenetic alterations emerge during T‑cell aging and repeated stimulation across both murine and human systems. Their research will quantify mutation burden in aging T cells and ISTCs, define how clonal repertoire and clonal hematopoiesis shift with age and stimulation, and map the epi-mutational changes that accompany iterative activation. A key question guiding this project is whether these epimutations are linked to cell‑cycle entry. Together, the team aims to establish a comprehensive framework for understanding how genetic and epigenetic processes shape T‑cell function, longevity, and long‑term genomic stability.

The third project, led by Jeffrey Rathmell, PhD, Denis Mogilenko, PhD, and Caitlin Zebley, MD, PhD, will investigate metabolic and mitochondrial integrity during iterative T-cell stimulation. To explore this hypothesis, the team will investigate how T cells respond to mitochondrial stress triggered by inflammation and fever, how epigenetic programs maintain T cell stemness and longevity, and how aging influences mitochondrial transfer between cells.

Together, these projects position the T-cell Longevity Collaborative to uncover the fundamental principles that allow T-cells to remain robust, adaptable, and safe across extraordinary cellular timespans. By integrating complementary expertise and innovative model systems, the Collaborative aims to enable life-long cancer-free maintenance of functional, highly proliferative T cells, and to translate these discoveries into approaches and metrics for developing and measuring safe, durable T-cell therapies for treating chronic infections and cancer.