Longitudinal analysis reveals age-related changes in the T cell receptor repertoire of human T cell subsets
Xiaoping Sun, … , Luigi Ferrucci, Nan-ping Weng
Xiaoping Sun, … , Luigi Ferrucci, Nan-ping Weng
Published June 16, 2022
Citation Information: J Clin Invest. 2022;132(17):e158122. https://doi.org/10.1172/JCI158122.
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Research Article Aging

Longitudinal analysis reveals age-related changes in the T cell receptor repertoire of human T cell subsets

Abstract

A diverse T cell receptor (TCR) repertoire is essential for protection against a variety of pathogens, and TCR repertoire size is believed to decline with age. However, the precise size of human TCR repertoires, in both total and subsets of T cells, as well as their changes with age, are not fully characterized. We conducted a longitudinal analysis of the human blood TCRα and TCRβ repertoire of CD4+ and CD8+ T cell subsets using a unique molecular identifier–based (UMI-based) RNA-seq method. Thorough analysis of 1.9 × 108 T cells yielded the lower estimate of TCR repertoire richness in an adult at 3.8 × 108. Alterations of the TCR repertoire with age were observed in all 4 subsets of T cells. The greatest reduction was observed in naive CD8+ T cells, while the greatest clonal expansion was in memory CD8+ T cells, and the highest increased retention of TCR sequences was in memory CD8+ T cells. Our results demonstrated that age-related TCR repertoire attrition is subset specific and more profound for CD8+ than CD4+ T cells, suggesting that aging has a more profound effect on cytotoxic as opposed to helper T cell functions. This may explain the increased susceptibility of older adults to novel infections.

Authors

Xiaoping Sun, Thomas Nguyen, Achouak Achour, Annette Ko, Jeffrey Cifello, Chen Ling, Jay Sharma, Toyoko Hiroi, Yongqing Zhang, Chee W. Chia, William Wood III, Wells W. Wu, Linda Zukley, Je-Nie Phue, Kevin G. Becker, Rong-Fong Shen, Luigi Ferrucci, Nan-ping Weng

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Figure 1

Experimental scheme.

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Experimental scheme. (A) Experimental design. Thirty healthy adults were...
(A) Experimental design. Thirty healthy adults were selected from participants of the Baltimore Longitudinal Study of Aging (BLSA). At each of 2 visits, weight and height were measured and fasting blood was drawn, and PBMCs were isolated and cryopreserved. From each sample, CBC counts were analyzed. For experiments, PBMCs were thawed and stained for CD4, CD8, CD45RA and CD28. Naive and memory CD4+ and CD8+ T cells were isolated by cell sorting for T cell receptor α (TCRα) and TCRβ repertoire analysis. PBMCs were isolated from 3 additional healthy adults and naive and memory CD4+ and CD8+ T cells were sorted in 3–4 aliquots as reproducibility controls. UMI, unique molecular identifier. (B) Age and sex of participants at first and second donation. Each line represents 1 donor, and the length of line indicates years between donations. (C–F) Numbers of lymphocytes, total, naive, and memory CD4+ and CD8+ T cells in samples from 2 donations, with change with age. Cell numbers were based on (a) lymphocyte counts per microliter of blood; (b) percentage of CD4+ and CD8+ T cells and naive and memory cells in lymphocytes, calculated from flow cytometry; and (c) blood volume calculated from donor weight and height adjusted by sex (39). Thin short lines link 2 donations from 1 participant. The thick long line is the trend from MLE analysis. The colored shade around the trend line indicates 95% confidence interval. Unless otherwise noted, values were transformed with log10 for presentation and statistical analysis. Values for slope (S) of the trend line and P values (≤ 0.05 was considered significant) are presented. N, naive; M, memory T cells.