The immunology of type 1 diabetes

Herold, Kevan C.; Delong, Thomas; Perdigoto, Ana Luisa; Biru, Noah; Brusko, Todd M.; Walker, Lucy S. K.

doi:10.1038/s41577-023-00985-4

Cited by 24 publications

(2 citation statements)

References 240 publications

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“…There are two main types of diabetes: type 1 diabetes (T1D) and type 2 diabetes (T2D). T1D develops when the immune system attacks and destroys pancreatic beta cells resulting in an inability of patients to produce insulin ( 88 ). T2D is characterized by a reduced production of insulin or a resistance to it, and is associated with obesity or high body fat percentage in the abdominal region ( 89 ).…”

Section: Il-3 In Diseasesmentioning

confidence: 99%

IL-3: key orchestrator of inflammation

Podolska,

Grützmann,

Pilarsky

et al. 2024

Front. Immunol.

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Interleukin (IL)-3 has long been known for its hematopoietic properties. However, recent evidence has expanded our understanding of IL-3 function by identifying IL-3 as a critical orchestrator of inflammation in a wide array of diseases. Depending on the type of disease, the course of inflammation, the cell or the tissue involved, IL-3 promotes either pathologic inflammation or its resolution. Here, we describe the cell-specific functions of IL-3 and summarize its role in diseases. We discuss the current treatments targeting IL-3 or its receptor, and highlight the potential and the limitations of targeting IL-3 in clinics.

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Section: Il-3 In Diseasesmentioning

confidence: 99%

IL-3: key orchestrator of inflammation

Podolska,

Grützmann,

Pilarsky

et al. 2024

Front. Immunol.

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“…Islet transplantation has become a promising therapy for certain endocrine disorders, particularly type 1 diabetes mellitus (T1DM), which affects approximately 1.6 million Americans, and the incidence of this disease continues to increase globally ( 1 – 3 ). Despite advances in insulin therapy and continuous glucose monitoring, achieving optimal glycemic control remains a challenge for many patients, leading to long-term complications and increased mortality ( 4 , 5 ). The limitations of current treatments underscore the urgent need for alternative approaches, such as islet transplantation, to restore endogenous insulin production and achieve tighter glycemic control.…”

Section: Introductionmentioning

confidence: 99%

Elucidating T cell dynamics and molecular mechanisms in syngeneic and allogeneic islet transplantation through single-cell RNA sequencing

Zhou,

Pu,

et al. 2024

Front. Immunol.

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Islet transplantation is a promising therapy for diabetes treatment. However, the molecular underpinnings governing the immune response, particularly T-cell dynamics in syngeneic and allogeneic transplant settings, remain poorly understood. Understanding these T cell dynamics is crucial for enhancing graft acceptance and managing diabetes treatment more effectively. This study aimed to elucidate the molecular mechanisms, gene expression differences, biological pathway alterations, and intercellular communication patterns among T-cell subpopulations after syngeneic and allogeneic islet transplantation. Using single-cell RNA sequencing, we analyzed cellular heterogeneity and gene expression profiles using the Seurat package for quality control and dimensionality reduction through t-SNE. Differentially expressed genes (DEGs) were analyzed among different T cell subtypes. GSEA was conducted utilizing the HALLMARK gene sets from MSigDB, while CellChat was used to infer and visualize cell-cell communication networks. Our findings revealed genetic variations within T-cell subpopulations between syngeneic and allogeneic islet transplants. We identified significant DEGs across these conditions, highlighting molecular discrepancies that may underpin rejection or other immune responses. GSEA indicated activation of the interferon-alpha response in memory T cells and suppression in CD4+ helper and γδ T cells, whereas TNFα signaling via NFκB was particularly active in regulatory T cells, γδ T cells, proliferating T cells, and activated CD8+ T cells. CellChat analysis revealed complex communication patterns within T-cell subsets, notably between proliferating T cells and activated CD8+ T cells. In conclusion, our study provides a comprehensive molecular landscape of T-cell diversity in islet transplantation. The insights into specific gene upregulation in xenotransplants suggest potential targets for improving graft tolerance. The differential pathway activation across T-cell subsets underscores their distinct roles in immune responses posttransplantation.

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LRH‐1/NR5A2 targets mitochondrial dynamics to reprogram type 1 diabetes macrophages and dendritic cells into an immune tolerance phenotype

Cobo‐Vuilleumier,

Rodríguez‐Fernandez,

López‐Noriega

et al. 2024

Clinical & Translational Med

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BackgroundThe complex aetiology of type 1 diabetes (T1D), characterised by a detrimental cross‐talk between the immune system and insulin‐producing beta cells, has hindered the development of effective disease‐modifying therapies. The discovery that the pharmacological activation of LRH‐1/NR5A2 can reverse hyperglycaemia in mouse models of T1D by attenuating the autoimmune attack coupled to beta cell survival/regeneration prompted us to investigate whether immune tolerisation could be translated to individuals with T1D by LRH‐1/NR5A2 activation and improve islet survival.MethodsPeripheral blood mononuclear cells (PBMCs) were isolated from individuals with and without T1D and derived into various immune cells, including macrophages and dendritic cells. Cell subpopulations were then treated or not with BL001, a pharmacological agonist of LRH‐1/NR5A2, and processed for: (1) Cell surface marker profiling, (2) cytokine secretome profiling, (3) autologous T‐cell proliferation, (4) RNAseq and (5) proteomic analysis. BL001‐target gene expression levels were confirmed by quantitative PCR. Mitochondrial function was evaluated through the measurement of oxygen consumption rate using a Seahorse XF analyser. Co‐cultures of PBMCs and iPSCs‐derived islet organoids were performed to assess the impact of BL001 on beta cell viability.ResultsLRH‐1/NR5A2 activation induced a genetic and immunometabolic reprogramming of T1D immune cells, marked by reduced pro‐inflammatory markers and cytokine secretion, along with enhanced mitohormesis in pro‐inflammatory M1 macrophages and mitochondrial turnover in mature dendritic cells. These changes induced a shift from a pro‐inflammatory to an anti‐inflammatory/tolerogenic state, resulting in the inhibition of CD4+ and CD8+ T‐cell proliferation. BL001 treatment also increased CD4+/CD25+/FoxP3+ regulatory T‐cells and Th2 cells within PBMCs while decreasing CD8+ T‐cell proliferation. Additionally, BL001 alleviated PBMC‐induced apoptosis and maintained insulin expression in human iPSC‐derived islet organoids.ConclusionThese findings demonstrate the potential of LRH‐1/NR5A2 activation to modulate immune responses and support beta cell viability in T1D, suggesting a new therapeutic approach.Key Points LRH‐1/NR5A2 activation in inflammatory cells of individuals with type 1 diabetes (T1D) reduces pro‐inflammatory cell surface markers and cytokine release. LRH‐1/NR5A2 promotes a mitohormesis‐induced immuno‐resistant phenotype to pro‐inflammatory macrophages. Mature dendritic cells acquire a tolerogenic phenotype via LRH‐1/NR5A2‐stimulated mitochondria turnover. LRH‐1/NR5A2 agonistic activation expands a CD4+/CD25+/FoxP3+ T‐cell subpopulation. Pharmacological activation of LRH‐1/NR5A2 improves the survival iPSC‐islets‐like organoids co‐cultured with PBMCs from individuals with T1D.

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The immunology of type 1 diabetes

Cited by 24 publications

References 240 publications

IL-3: key orchestrator of inflammation

IL-3: key orchestrator of inflammation

Elucidating T cell dynamics and molecular mechanisms in syngeneic and allogeneic islet transplantation through single-cell RNA sequencing

LRH‐1/NR5A2 targets mitochondrial dynamics to reprogram type 1 diabetes macrophages and dendritic cells into an immune tolerance phenotype

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