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A novel subpopulation of monocytes with a strong interferon signature indicated by SIGLEC-1 is present in patients with in recent-onset type 1 diabetes

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Abstract

Aims/hypothesis

Type 1 diabetes is a T cell-mediated autoimmune disease characterised by pancreatic beta cell destruction. In this study, we explored the pathogenic immune responses in initiation of type 1 diabetes and new immunological targets for type 1 diabetes prevention and treatment.

Methods

We obtained peripheral blood samples from four individuals with newly diagnosed latent autoimmune diabetes in adults (LADA) and from four healthy control participants. Single-cell RNA-sequencing (scRNA-seq) was performed on peripheral blood mononuclear cells to uncover transcriptomic profiles of early LADA. Validation was performed through flow cytometry in a cohort comprising 54 LADA, 17 adult-onset type 2 diabetes, and 26 healthy adults, matched using propensity score matching (PSM) based on age and sex. A similar PSM method matched 15 paediatric type 1 diabetes patients with 15 healthy children. Further flow cytometry analysis was performed in both peripheral blood and pancreatic tissues of non-obese diabetic (NOD) mice. Additionally, cell adoptive transfer and clearance assays were performed in NOD mice to explore the role of this monocyte subset in islet inflammation and onset of type 1 diabetes.

Results

The scRNA-seq data showed that upregulated genes in peripheral T cells and monocytes from early-onset LADA patients were primarily enriched in the IFN signalling pathway. A new cluster of classical monocytes (cluster 4) was identified, and the proportion of this cluster was significantly increased in individuals with LADA compared with healthy control individuals (11.93% vs 5.93%, p=0.017) and that exhibited a strong IFN signature marked by SIGLEC-1 (encoding sialoadhesin). These SIGLEC-1+ monocytes expressed high levels of genes encoding C-C chemokine receptors 1 or 2, as well as genes for chemoattractants for T cells and natural killer cells. They also showed relatively low levels of genes for co-stimulatory and HLA molecules. Flow cytometry analysis verified the elevated levels of SIGLEC-1+ monocytes in the peripheral blood of participants with LADA and paediatric type 1 diabetes compared with healthy control participants and those with type 2 diabetes. Interestingly, the proportion of SIGLEC-1+ monocytes positively correlated with disease activity and negatively with disease duration in the LADA patients. In NOD mice, the proportion of SIGLEC-1+ monocytes in the peripheral blood was highest at the age of 6 weeks (16.88%), while the peak occurred at 12 weeks in pancreatic tissues (23.65%). Adoptive transfer experiments revealed a significant acceleration in diabetes onset in the SIGLEC-1+ group compared with the SIGLEC-1− or saline control group.

Conclusions/interpretation

Our study identified a novel group of SIGLEC-1+ monocytes that may serve as an important indicator for early diagnosis, activity assessment and monitoring of therapeutic efficacy in type 1 diabetes, and may also be a novel target for preventing and treating type 1 diabetes.

Data availability

RNA-seq data have been deposited in the GSA human database (https://ngdc.cncb.ac.cn/gsa-human/) under accession number HRA003649.

Graphical Abstract

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Abbreviations

CD11b:

αM-integrin

cDC2:

Conventional type 2 dendritic cell

DEG:

Differentially expressed gene

FCM:

Flow cytometry

GADA:

GAD65 antibody

GDT:

γδ T cell

GO:

Gene Ontology

ICR:

Institute of Cancer Research

LADA:

Latent autoimmune diabetes in adults

Lin:

Lineage

Ly6c:

Lymphocyte antigen 6 complex locus C

MAIT:

Mucosal-associated invariant T cell

MX1:

Myxovirus Resistance 1

NK:

Natural killer cell

NKT:

Natural killer T cell

NOD:

Non-obese diabetic

PBMC:

Peripheral blood mononuclear cell

pDC:

Plasmacytoid dendritic cell

PLXNB2:

Plexin B2

PSM:

Propensity score matching

scRNA-seq:

Single-cell RNA-sequencing

Sema4D:

Semaphorin 4D

SIGLEC-1:

Sialoadhesin

STAT1:

Signal transducer and activator of transcription 1

Teff:

Effector T cell

Tem:

Effector memory T cell

Treg:

Regulatory T cell

UMAP:

Uniform Manifold Approximation and Projection

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Author notes

  1. Mengqi Guo, Han Guo and Jingjing Zhu contributed equally to this work.

Authors and Affiliations

  1. Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China

    Mengqi Guo, Han Guo, Jingjing Zhu, Fei Wang, Jianni Chen, Chuan Wan, Yujie Deng, Fang Wang, Lili Xu, Ying Chen, Ran Li, Yangang Wang & Shufa Li

  2. Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China

    Mengqi Guo

  3. Key Laboratory of Mariculture, Ministry of Education College of Fisheries, Ocean University of China, Qingdao, China

    Shikai Liu

  4. Department of Pharmacy, Shaoxing People’s Hospital, Shaoxing, Zhejiang Province, China

    Lin Zhang

  5. Institute of Immunology, Third Military Medical University, Chongqing, China

    Jing Zhou

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  1. Mengqi Guo
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Corresponding authors

Correspondence to Yangang Wang, Jing Zhou or Shufa Li.

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Acknowledgements

We would like to thank X. Jiang of the Third Military Medical University, China, for his help in the experiments. We also thank all the participants who made this research possible.

Data availability

RNA-seq data have been deposited in the GSA human database (https://ngdc.cncb.ac.cn/gsa-human/) under accession number HRA003649.

Funding

This study was supported by the National Natural Science Foundation of China (grant numbers 81570694 and 82000417) and the Natural Science Foundation of Shandong (grant number ZR2014HL029).

Authors’ relationships and activities

MQG, FW (Fei Wang), YJD, FW (Fang Wang), LLX, YC, RL, YGW and SFL are current employees at the Affiliated Hospital of Qingdao University, China. The other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Contribution statement

SFL, YGW and JZ were responsible for study conception and design. JNC, CW, YJD, FW (Fei Wang), FW (Fang Wang), LZ, HG, JJZ, RL and SKL were responsible for data acquisition and analysis. MQG, LLX and YC performed the data interpretation. MQG, LLX, YC and FW (Fei Wang) drafted the article. SFL, YGW, JZ, JNC, CW, YJD, FW (Fang Wang), LZ, HG, JJZ, RL and SKL critically reviewed the article. All authors approved the final version of this manuscript to be published. SFL is responsible for the integrity of the work as a whole.

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Guo, M., Guo, H., Zhu, J. et al. A novel subpopulation of monocytes with a strong interferon signature indicated by SIGLEC-1 is present in patients with in recent-onset type 1 diabetes. Diabetologia 67, 623–640 (2024). https://doi.org/10.1007/s00125-024-06098-4

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