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Characteristics of T cell premature senescence in maintenance hemodialysis patients

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Abstract

Background

Uremia-associated immunodeficiency, mainly characterized by T cell dysfunction, exists in patients on maintenance hemodialysis (MHD) and promotes systemic inflammation. However, T cell senescence, one of the causes of T cell dysfunction, has not been clearly revealed yet. In this cross-sectional research, we aimed to study the manifestation of T cell premature senescence in MHD patients and further investigate the associated clinical factors.

Methods

76 MHD patients including 33 patients with cardiovascular diseases (CVD) and 28 patients with arteriovenous fistula (AVF) event history were enrolled in this study. Complementarity determining region 3 (CDR3) of T cell receptor (TCR) was analyzed by immune repertoire sequencing (IR-Seq). CD28- T cell subsets and expression of senescence marker p16 and p21 genes were detected by multicolor flow cytometry and RT-qPCR, respectively.

Results

MHD patients had significantly decreased TCR diversity (P < 0.001), increased CDR3 clone proliferation (P = 0.001) and a left-skewed CDR3 length distribution. The proportion of CD4 + CD28- T cells increased in MHD patients (P = 0.014) and showed a negative correlation with TCR diversity (P = 0.001). p16 but not p21 expression in T cells was up-regulated in MHD patients (P = 0.039). Patients with CVD exhibited increased expression of p16 and p21 genes (P = 0.010 and 0.004, respectively), and patients with AVF events showed further TCR diversity and evenness reduction (P = 0.002 and 0.017, respectively) compared to patients without the comorbidities. Moreover, age, average convection volume, total cholesterol, high-density lipoprotein cholesterol and transferrin saturation were associated with TCR diversity or CD4 + CD28- T cell proportion (P < 0.05).

Conclusions

MHD patients undergo T cell premature senescence characterized by significant TCR diversity reduction and repertoire skew, as well as accumulation of the CD4 + CD28- subset and up-regulation of p16 gene. Patients with CVD or AVF events show higher level of immunosenescence. Furthermore, T cell senescence in MHD patients is associated with blood cholesterol and uremic toxin retention, suggesting potential intervention strategies in the future.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We appreciate all the patients and healthy volunteers who willingly participated and were involved in this study.

Funding

This study was funded by the National Natural Science Foundation of China (81970610, 82000634), the Shanghai Science/Technology Commission/Animal Special Program (22140903900), the Program of Shanghai Academic/Technology Research Leader (22XD1431400), the Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant (20172015) and Shanghai Sailing Program (20YF1425000).

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Author notes

  1. Wangshu Wu, Ahui Song and Kewei **e contributed equally to this work.

Authors and Affiliations

  1. Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University School of Medicine, 160# Pujian Road, Building 1, 2nd Floor, Shanghai, 200127, China

    Wangshu Wu, Ahui Song, Kewei **e, Jiayue Lu, Bingru Zhao, Cheng Qian, Minzhou Wang, Lulin Min, Wenkai Hong, Huihua Pang, Renhua Lu & Leyi Gu

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  1. Wangshu Wu
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Contributions

All authors contributed to the study conception and design. LG designed the study. WW, AS, KX, HP, RL and LG were responsible for the subject recruitment and the informed consent. WW, AS, KX, JL, BZ, CQ, MW, LM and WH were responsible for clinical data collection and validation. WW, AS, KX, JL and BZ conducted the laboratory tests and statistical analysis. WW, AS and KX wrote the original draft. LG, RL and HP revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Huihua Pang, Renhua Lu or Leyi Gu.

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Ethics approval

This study was approved by the Ethics Committee of Shanghai Jiao Tong University School of Medicine, Renji Hospital (LY2023-098-B). All the participants provided written informed consent.

Competing interests

The authors declare no competing interests.

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The authors have no relevant financial or non-financial interests to disclose.

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Communicated by L Li.

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Wu, W., Song, A., **e, K. et al. Characteristics of T cell premature senescence in maintenance hemodialysis patients. Inflamm. Res. (2024). https://doi.org/10.1007/s00011-024-01897-2

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