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Decreased expression of programmed death-1 on CD8+ effector memory T lymphocytes correlates with the pathogenesis of type 1 diabetes

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Abstract

Aims

Chronic inflammation of autoimmune diseases, including type 1 diabetes (T1D), is mainly mediated by memory T(Tm) cells, predominantly effector memory T (Tem) cells. The roles of the programmed death-1 (PD-1) receptor on lymphocytes have been well studied in tumor and other infection models. However, little is known about the relationship between the expression of PD-1 on CD8+ Tem cells and the pathogenesis of T1D.

Methods

A total of 52 patients diagnosed with T1D and 39 gender-, age-, and ethnically matched health control individuals were enrolled in this study. Peripheral blood mononuclear cells from these individuals were isolated and analyzed by flow cytometry. We evaluated the frequencies of PD-1+ CD8+ memory T cell subsets from patients' peripheral blood with T1D and the spleen cells of nonobese diabetic (NOD) mice in the present study. We also investigated the effects of blocking PD-1/PD-L1 pathway on islet’s inflammation in NOD mice.

Results

Frequencies of PD-1+ CD8+ Tem cells were decreased significantly in PBMC of patients with T1D (40.73 ± 12.72 vs 47.43 ± 15.56, *p < 0.05). The frequencies of PD-1+ CD8+ Tem cells were decreased in patients with T1D who were positive for two or more autoantibodies compared with the patients with one autoantibody (13.46% vs 46.95 ± 12.72%, *p < 0.05). Meanwhile, the frequencies of PD-1+ CD8+ central memory T (Tcm) cells were also significantly decreased in patients with two or more autoantibodies compared with other groups (≥ 2AAb vs HC 33.1 ± 8.92% vs 43.71 ± 11.78%, *p < 0.05; ≥ 2AAb vs AAb—33.1 ± 8.92% vs 41.65 ± 11.2%, *p < 0.05; ≥ 2AAb vs 1AAb 33.1 ± 8.92% vs 48.09 ± 10.58%, ***p < 0.001). The frequencies of PD-1+CD8+ Tem cells were positively correlated with fasting serum C-peptide levels (r = 0.4308, *p < 0.05) and C-peptide levels 2 h after meal in T1D patients (r = 0.5723, **p < 0.01). The frequencies of PD-1+CD8+ Tcm cells were only negatively correlated with the levels of HbA1c (r = − 0.2992, *p < 0.05). Similarly, the frequencies of PD-1+CD8+ Tem were significantly decreased in intervention group (anti-mouse PD-1 mAb) compared with the control group (14.22 ± 6.455% vs 27.69 ± 9.837%, *p < 0.05). Pathologically, CD8, PD-1 and PD-L1 were strongly expressed in the islets of diabetic mice after PD-1 blockade.

Conclusions

It is the first report of the expression of PD-1 on CD8+ Tem cells in T1D in the present study. Our observations suggest that the PD-1/PD-L1 signal pathway on CD8+ Tem cells of T1D subjects might identify a new pathway for delaying the occurrence and development by inhibiting autoimmunity.

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The data are available on request from the authors.

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Acknowledgements

The authors thank all patients and health providers involved in this study. The work was supported by grants from the National Natural Science Foundation of China (Grant numbers 82070814), Scientific Research Project of Jiangsu Health Commission (Grant Numbers H2019043), Scientific Research Project of Suzhou Health Commission (Grant Numbers SYS2019070), Open project of the State Key Laboratory of Radiation Medicine and Radiation Protection jointly built by the Ministry and the province (Grant Numbers GZK1202025), Second Affiliated Hospital of Soochow University Science Foundation (Grant numbers SDFEYQN1912) and Suzhou Science and Education Health Project (Grant Numbers kjxw2019015).

Funding

The work was supported by grants from the National Natural Science Foundation of China (Grant numbers 82070814), Scientific Research Project of Jiangsu Health Commission (Grant Numbers H2019043), Scientific Research Project of Suzhou Health Commission (Grant Numbers SYS2019070), Open project of the State Key Laboratory of Radiation Medicine and Radiation Protection jointly built by the Ministry and the province (Grant Numbers GZK1202025), Second Affiliated Hospital of Soochow University Science Foundation (Grant numbers SDFEYQN1912), and Suzhou Science and Education Health Project (Grant Numbers kjxw2019015). These funders were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report.

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Authors and Affiliations

  1. Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, China

    Yimei Shan, Yan Zhou, Jingjing Guo, Qiyun Shi, Sicheng Li, Heming Guo, Yun Huang, Chen Fang & Ji Hu

  2. Department of Endocrinology, Changshu No. 2 People’s Hospital, Changshu, China

    Yinghong Kong

  3. Clinical Medicine Research Center, Affiliated Hospital 2 of Nantong University, Nantong, China

    Yimei Shan

  4. Department of Clinical Nutrition, The Second Affiliated Hospital of Soochow University, Suzhou, China

    Yiting Huang & Chen Fang

  5. Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China

    Sisi Ding, Cuiping Liu & Lei Cao

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  1. Yimei Shan
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Contributions

CF and JH conceived and designed the study. YMS and YHK analyzed the data and drafted the article. YZ, JJG, QYS, SCL, HMG, and YTH contributed to acquisition of the data. CPL, LC, SSD, YH, CF, and JH revised the article critically for important intellectual content and interpreted the data. All authors read and approved the final version for submission.

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Correspondence to Chen Fang or Ji Hu.

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The authors declare that they have no conflict of interest.

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All procedures performed involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from the patient.

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Yimei Shan and Yinghong Kong contributed equally to this work.

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Shan, Y., Kong, Y., Zhou, Y. et al. Decreased expression of programmed death-1 on CD8+ effector memory T lymphocytes correlates with the pathogenesis of type 1 diabetes. Acta Diabetol 58, 1239–1249 (2021). https://doi.org/10.1007/s00592-021-01711-z

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