Heterogeneity of thymic output in the elderly and its association with sex and smoking
Balraj Sandhar, Vishal Vyas, Daniel Harding, Roberta Ragazzini, Paola Bonfanti, Federica M. Marelli-Berg, Christopher G. Bell, Benny M. Chain, M. Paula Longhi
Balraj Sandhar, Vishal Vyas, Daniel Harding, Roberta Ragazzini, Paola Bonfanti, Federica M. Marelli-Berg, Christopher G. Bell, Benny M. Chain, M. Paula Longhi
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Clinical Research and Public Health Cardiology Immunology

Heterogeneity of thymic output in the elderly and its association with sex and smoking

Abstract

BACKGROUND Thymic involution with age leads to reduced T cell output and impaired adaptive immunity. However, the extent to which thymic activity persists later in life and how this contributes to immunological aging remains unclear. This study aimed to assess the presence and function of thymic tissue in older adults and identify factors influencing residual thymopoiesis.METHODS Patients aged 50 or older undergoing cardiothoracic surgery were recruited. Thymic structures within mediastinal adipose tissue were evaluated using histology, immunofluorescence, flow cytometry, T cell receptor (TCR) sequencing, and RNA sequencing. Recent thymic emigrants (RTEs) were quantified in peripheral blood and correlated with transcriptomic, epigenetic, and TCR repertoire data. Primary outcomes included thymic tissue identification, RTE frequency, and immune correlates.RESULTS Functional thymic tissue was identified in mediastinal adipose tissue of older individuals. The frequency of CD31+CD4+ T cells (RTEs) positively correlated with the presence of thymic tissue. Thymic output showed substantial heterogeneity and was influenced by sex and smoking history. Thymic activity was associated with increased TCR repertoire diversity, improved immune protection against infections, and reduced epigenetic aging. Detailed profiling uncovered functional and phenotypic heterogeneity within naive CD4+ T cell subsets shaped by thymic activity.CONCLUSION This study demonstrates that thymic function can persist into later life and is modulated by factors such as sex and smoking. These findings suggest that thymic activity during aging is heterogeneous and influenced by more than chronological age alone, with potential implications for immune competence in older adults.

Authors

Balraj Sandhar, Vishal Vyas, Daniel Harding, Roberta Ragazzini, Paola Bonfanti, Federica M. Marelli-Berg, Christopher G. Bell, Benny M. Chain, M. Paula Longhi

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Figure 2

Thymic output correlates to peripheral T cell subpopulation and associates with sex and smoking in older patients.

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Thymic output correlates to peripheral T cell subpopulation and associat...
(A) Proportion of CD4+ and (B) CD8+ naive, TCM, TEM, and TEMRA cells in the blood of patients classified as either thymic+ or thymic–. Data presented as mean ± SD. Statistical significance evaluated by 2-way ANOVA with Šídák’s multiple-comparison test. (C) Linear regression analysis comparing RTE% in blood to peripheral T cell pools. (D) Correlative linear regression analysis between chronological age and RTE% in blood for individuals aged <50 years (young; green) (n = 35) and ≥50 years (old; purple) (n = 110). (E) Correlation matrix comparing clinical characteristics to thymic output (relative RTE%) and naive T cell percentage in the blood of patients ≥50 years. Spearman’s coefficients with Bonferroni’s correction P value cutoff <0.002. Significant correlation coefficients are shown as either blue (positive correlation) or red (negative correlation) dots. (F) Graph illustrating RTE% in blood between smokers and nonsmokers and males and females. Truncated violin plots show medians and interquartile ranges, and significance was evaluated by 2-tailed Mann-Whitney U test. The r2 values in D and E were calculated using Pearson’s correlation coefficients and significance by 2-sided P value analysis.