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Heterogeneity of circulating CXCR5-PD-1hiTph cells in patients of type 2 and type 1 diabetes in Chinese population

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Abstract

Aims

Circulating peripheral helper T (Tph) cells are shown to promote the progression of autoimmune diseases. However, the role of Tph cells in inflammatory diseases such as type 2 diabetes mellitus (T2DM) and the differences between T2DM and autoimmune diabetes remain unclear.

Methods

We recruited 92 T2DM patients, 106 type 1 diabetes mellitus (T1DM) patients and 84 healthy control individuals. Peripheral blood mononucleated cells were isolated and examined by multicolor flow cytometry. We further evaluated the correlations between circulating Tph cells and clinical biochemical parameters, islet function, disease progression and islet autoantibodies.

Results

Circulating Tph cells were significantly higher in both T2DM and T1DM patients than in healthy control individuals. A significant positive correlation was observed between Tph cells and B cells in T1DM patients and overweight T2DM patients. Furthermore, Tph cells were negatively correlated with the area under the C-peptide curve (C-PAUC), and Tph cells were significantly positively correlated with fasting glucose and glycated hemoglobin levels in T2DM patients. However, no correlation was found between Tph cells and the above clinical indicators in T1DM patients. The frequency of Tph cells positively correlated with the titer of GAD autoantibodies and duration of disease in T1DM patients. In addition, we demonstrated that the frequency of Tph cells was decreased after rituximab therapy in T1DM patients.

Conclusions

Circulating Tph cells are associated with blood glucose levels and islet function in T2DM patients. In T1DM patients, circulating Tph cells are associated with B cells and islet autoantibodies. This may suggest that Tph cells have different pathogenic mechanisms in the two types of diabetes.

Clinical trial information

http://ClinicalTrials.gov NCT01280682 (registered July, 2010).

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Data availability

The datasets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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Funding

This study was supported by grants from the National Natural Science Foundation of China (number 81970707, 82270875,82230028).

Author information

Authors and Affiliations

  1. Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China

    Zhangyao Su, Chenggong Ma, Ruiling Zhao, Yin Jiang, Yun Cai, Gu Yong, Tao Yang & Xinyu Xu

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Contributions

ZS and XX performed the experiments. YC, CM and YG provided the clinical samples. RZ and YJ were responsible for the analyses of diabetes-associated autoantibodies. ZS and XX analyzed the data and drafted the manuscript. All authors contributed to the final version of the manuscript. TY and XX are the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Corresponding authors

Correspondence to Tao Yang or Xinyu Xu.

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Conflict of interest

The authors declare that they have no conflict of interest.

Statement of human and animal rights

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Local Ethics Committee of First Affiliated Hospital of Nanjing Medical University.

Informed consent

The study was based on the collection of data generated by observation and follow-up study of immunological markers in patients with type 1 diabetes and first-degree relatives. Thus, informed consent was signed.

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Supplementary Information

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Supplementary Fig. S1

Representative dot plot showing the gating strategy for Tfh cells and FOXP3+CXCR5+PD-1+Tfr cells. (TIF 4346 KB)

Supplementary Fig. S2

The frequency of circulating Tph cells did not correlate with (A) B cells but did correlate with the frequency of (B) Tfh cells and (C) FOXP3+CXCR5+PD-1+ Tfr cells in T2DM patients (n = 92). The frequency of circulating Tph cells was positively correlated with the frequency of (D) B cells, (E) Tfh cells and (F) FOXP3+CXCR5+PD-1+ Tfr cells in T1DM patients (n = 106). Correlations between circulating CXCR5-PD-1hi Tph cells and PD-1+Tfh/Tfr ratio in patients with (G) T2DM (n = 92) and (J) T1DM (n=106). Correlations between circulating Tph cells and FOXP3+CXCR5+ICOS+ Tfr cells in patients with (H) T2DM (n = 92) and (K) T1DM (n = 106). Correlations between Tph cells and Treg cells in (I) T2DM (n = 92) and (L) T1DM patients (n = 106). (TIF 4464 KB)

Supplementary Fig. S3

(A–C) Correlations between circulating Tph cells and (A) BMI, (B) B cells, (C) Tfh cells and (D) FOXP3+CXCR5+PD-1+ Tfr cells in normal weight T2DM patients (n = 33). (E–F) Correlations between circulating Tph cells and FOXP3+CXCR5+ICOS+ Tfr cells in (E) normal weight T2DM patients (n = 33) and (F) overweight T2DM patients (n = 59). (TIF 2174 KB)

Supplementary Fig. S4

(A–C) Correlation between circulating Tph cells and the levels of (A) C-PAUC, (B) fasting blood glucose and (C) HbA1c in normal weight T2DM patients (n = 33). (D–E) Correlations between circulating Tph cells and fasting serum C-peptide in (D) overweight T2DM patients (n = 59) and (E) normal weight T2DM patients (n = 33). (F) Correlation between circulating Tph cells and disease course in T2DM patients (n = 92). (G–H) Correlations between circulating Tph cells and HOMA-IR in (G) T2DM patients, (H) overweight T2DM patients (n = 59) and (I) normal weight T2DM patients (n = 33). (TIF 2916 KB)

Supplementary Fig. S5

(A–D) Correlation between the frequency of circulating Tph cells and (A) the level of C-P (n = 68), (B) C-PAUC (n = 53), (C) fasting blood glucose (n = 66) and (D) HbA1c (n = 96) in T1DM patients. (E–F) Correlation between the frequency of circulating Tph cells and (E) disease duration (n = 84) and (F) daily insulin dose in T1DM patients (n = 91). (TIF 2902 KB)

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Su, Z., Ma, C., Zhao, R. et al. Heterogeneity of circulating CXCR5-PD-1hiTph cells in patients of type 2 and type 1 diabetes in Chinese population. Acta Diabetol 60, 767–776 (2023). https://doi.org/10.1007/s00592-023-02055-6

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