Nonlinear Aging of the Human TCR Repertoire Is Influenced by Sex, CMV, and Cancer
8 affiliations
- 1Department of Molecular Medicine (MOMA) Aarhus University Hospital Aarhus Denmark
- 2Department of Clinical Medicine Aarhus University Aarhus Denmark
- 3Department of Health Technology, Section for Bioinformatics Technical University of Denmark, DTU Lyngby Denmark
- 4Cancer Research UK Lung Cancer Centre of Excellence University College London Cancer Institute London UK
- 5Cancer Genome Evolution Research Group University College London Cancer Institute London UK
- 6Artificial Intelligence in Medicine (AIM) Program Mass General Brigham, Harvard Medical School Boston Massachusetts USA
- 7Department of Radiation Oncology Brigham and Women's Hospital and Dana‐Farber Cancer Institute, Harvard Medical School Boston Massachusetts USA
- 8Radiology and Nuclear Medicine GROW & CARIM, Maastricht University Maastricht the Netherlands
Abstract
Aging is accompanied by a progressive decline in immune function, increasing susceptibility to infections, cancer, and poorer treatment outcomes. The diversity of the T cell receptor (TCR) repertoire, reflecting the capacity to recognize diverse antigens, is known to decline with age. However, how intrinsic and extrinsic factors jointly shape TCR diversity and its rate of decline, as well as the extent to which this diversity influences clinical outcomes in cancer, remain poorly characterized. Here, we integrate TCR sequencing data from 1.32 billion unique T cell clones, derived from 798 patients with cancer and 5052 individuals without cancer across 14 independent cohorts, to systematically characterize the effects of age, sex, and chronic cytomegalovirus (CMV) infection on peripheral blood repertoire diversity. We identify a nonlinear trajectory of diversity loss that accelerates after midlife, with a marked increase in the rate of decline beyond approximately 50 years of age, which is further modified by sex and CMV infection. In patients with cancer, higher peripheral TCR diversity was associated with improved overall survival across multiple cancer types, even when accounting for the impact of age, sex, and CMV on diversity. Together, these findings underline peripheral TCR repertoire diversity as a dynamic marker of immune aging shaped by demographic and chronic viral factors.
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BibTeX
@article{lange2026nonlinear,
title = {{Nonlinear Aging of the Human TCR Repertoire Is Influenced by Sex, CMV, and Cancer}},
author = {Naja Lange and Asbjørn K. Attermann and Randi Istrup Juul and Laura Andersen and Iver Nordentoft and Leon Eyrich Jessen and Nicholas McGranahan and Hugo J. W. L. Aerts and Lars Dyrskjøt and Nicolai J. Birkbak},
journal = {Aging Cell},
year = {2026},
month = oct,
doi = {10.1111/acel.70777},
url = {https://doi.org/10.1111/acel.70777},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Nonlinear Aging of the Human TCR Repertoire Is Influenced by Sex, CMV, and Cancer
AU - Naja Lange
AU - Asbjørn K. Attermann
AU - Randi Istrup Juul
AU - Laura Andersen
AU - Iver Nordentoft
AU - Leon Eyrich Jessen
AU - Nicholas McGranahan
AU - Hugo J. W. L. Aerts
AU - Lars Dyrskjøt
AU - Nicolai J. Birkbak
PY - 2026
DA - 2026/10/25
JO - Aging Cell
DO - 10.1111/acel.70777
UR - https://doi.org/10.1111/acel.70777
AB - Aging is accompanied by a progressive decline in immune function, increasing susceptibility to infections, cancer, and poorer treatment outcomes. The diversity of the T cell receptor (TCR) repertoire, reflecting the capacity to recognize diverse antigens, is known to decline with age. However, how intrinsic and extrinsic factors jointly shape TCR diversity and its rate of decline, as well as the extent to which this diversity influences clinical outcomes in cancer, remain poorly characterized. Here, we integrate TCR sequencing data from 1.32 billion unique T cell clones, derived from 798 patients with cancer and 5052 individuals without cancer across 14 independent cohorts, to systematically characterize the effects of age, sex, and chronic cytomegalovirus (CMV) infection on peripheral blood repertoire diversity. We identify a nonlinear trajectory of diversity loss that accelerates after midlife, with a marked increase in the rate of decline beyond approximately 50 years of age, which is further modified by sex and CMV infection. In patients with cancer, higher peripheral TCR diversity was associated with improved overall survival across multiple cancer types, even when accounting for the impact of age, sex, and CMV on diversity. Together, these findings underline peripheral TCR repertoire diversity as a dynamic marker of immune aging shaped by demographic and chronic viral factors.
SN - 1474-9718
SN - 1474-9726
ER -