Abstract
We present an integrated analysis of the clinical measurements, immune cells, and plasma lipidomics of 2000 individuals representing different age stages. In the study, we explore the interplay of systemic lipids metabolism and circulating immune cells through in-depth analysis of immune cell phenotype and function in peripheral dynamic lipids environment. The population makeup of circulation lymphocytes and lipid metabolites changes dynamically with age. We identified a major shift between young group and middle age group, at which point elevated, immune response is accompanied by the elevation of specific classes of peripheral phospholipids. We tested the effects in mouse model and found that 10-month-dietary added phospholipids induced T-cell senescence. However, the chronic malignant disease, the crosstalk between systemic metabolism and immunity, is completely changed. In cancer patients, the unusual plasma cholesteryl esters emerged, and free fatty acids decreased. The study reveals how immune cell classes and peripheral metabolism coordinate during age acceleration and suggests immune senescence is not isolated, and thus, system effect is the critical point for cell- and function-specific immune-metabolic targeting.
Graphical abstract
• The study identifies a major shift of immune phenotype between young group and middle age group, and the immune response is accompanied by the elevation of specific classes of peripheral phospholipids;
• The study suggests potential implications for translational studies such as using metabolic drug to regulate immune activity.
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Acknowledgements
This work was supported by the Science and Technology Commission of Shanghai Municipality (21Y11902000) and the Shanghai Municipal Science and Technology Major Project (ZD2021CY001). The funding agencies had no role in the preparation, review or approval of the manuscript.
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MM and YY collected clinical blood samples and performed flow cytometry analysis. ZC performed animal experiments and data analysis. XZ was responsible for bioinformatics analysis. YY, ZC, and XZ wrote the original manuscript and contributed equally. XL and ZY designed the whole project and helped with data analysis. KW and XL were involved in data interpretation. HF, YC, and TQ assisted in the collection of clinical blood samples and research conception. ZL, XW, and DW revised the manuscript. All authors discussed the results and approved the manuscript.
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Experiments included in this study were approved by Jingshan Hospital, Fudan University Ethical Committee.
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10565_2023_9811_MOESM2_ESM.pptx
Supplementary file2 Supplemental Figure 1: The mean fluorescence intensity (MFI) of several key markers related to cell differentiation in different age groups of the immunonormal controls. A-K, MFI of biomarkers of CD3+T cells. L-N, MFI of biomarkers of CD3- cells. p<0.05 was considered statistically significant. *p<0.05; **p<0.01. ***p<0.0001. Supplemental Figure 2. (A) There are totally 26 clinical metadata factors. The pearson correlation between each pair of them were calculated using ‘cov’ function of R. The corresponding p-values between 0.05-0.01 was annotated with ‘*’, 0.01-0.001 with ‘**’, <0.001 with ‘***’. (B-K) The representative dot plot of flow cytometry and gating strategy of cell subsets for each group. The statistic data is summarized in Table 1. Supplemental Figure 3. The comparison of Mitored, Mitogreen MFI in total T cells, TH (CD4+T) cells and TC (CD8+T) cells of PBMCs between groups (<45 and >45). MFI: mean fluorescence intensity. Supplemental Figure 4. The plasma cytokines level and mean fluorescence intensity (MFI) of several key markers related to cell differentiation in immunonormal controls and tumor patients. A-K, MFI of biomarkers of CD3+T cells. L-N, MFI of biomarkers of CD3- cells. p<0.05 was considered statistically significant. *p<0.05; **p<0.01. ***p<0.0001. Supplemental Figure 5. System lipids characteristics of cancer patients. (A)Heatmap of 3 plasma lipid clusters detection for cancer patients. The heat map demonstrates the different level of listed lipid species between clusters. (B) Furthermore, we map the correlation between lipids with T cell subtypes. Linear regression analysis indicates that FFA (24:0) and FFA (20:3) correlate with TH and memory Treg cells. (PPTX 3.20 MB)
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Ma, M., Yang, Y., Chen, Z. et al. T-cell senescence induced by peripheral phospholipids. Cell Biol Toxicol 39, 2937–2952 (2023). https://doi.org/10.1007/s10565-023-09811-y
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DOI: https://doi.org/10.1007/s10565-023-09811-y