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The immunology of type 1 diabetes

Nature Reviews Immunology (2024)Cite this article

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Abstract

Following the seminal discovery of insulin a century ago, treatment of individuals with type 1 diabetes (T1D) has been largely restricted to efforts to monitor and treat metabolic glucose dysregulation. The recent regulatory approval of the first immunotherapy that targets T cells as a means to delay the autoimmune destruction of pancreatic β-cells highlights the critical role of the immune system in disease pathogenesis and tends to pave the way for other immune-targeted interventions for T1D. Improving the efficacy of such interventions across the natural history of the disease will probably require a more detailed understanding of the immunobiology of T1D, as well as technologies to monitor residual β-cell mass and function. Here we provide an overview of the immune mechanisms that underpin the pathogenesis of T1D, with a particular emphasis on T cells.

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Fig. 1: Risk genes for type 1 diabetes encode proteins that impact T cell development and function.
Fig. 2: The influence of the microbiome in T1D.
Fig. 3: Insulitis and CD8+ T cells in type 1 diabetes.
Fig. 4: T cell phenotypes associated with B cell help are linked to T1D.
Fig. 5: Disease-relevant hybrid insulin peptides (HIPs).
Fig. 6: Drugs and mechanisms that have shown efficacy in T1D.
Fig. 7: Mechanism of action of the CD3-targeting monoclonal antibody teplizumab.

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Acknowledgements

K.C.H. acknowledges support from the US National Institutes of Health (NIH) through grant numbers DK057846, DK129523, DK045735, AI66387, DK106993 (Type 1 Diabetes TrialNet) and CA2277473. A.L.P. also acknowledges support from NIH through grant numbers DK106993 (Type 1 Diabetes TrialNet) and CA215110. T.M.B. acknowledges support from the National Institutes of Allergy and Infectious Diseases (NIAID) through grant number P01AI042288 and National Institute of Diabetes Digestive and Kidney Diseases through grant numbers DK106191 and DK122638. L.S.K.W. acknowledges support from the Medical Research Council (MR/N001435/1), Wellcome Trust (220772/Z/20/Z), Diabetes UK (20/0006172) and Connect Immune Research (22931). We are grateful to Natalie Edner for the assistance with figure preparation.

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Authors and Affiliations

  1. Department of Immunobiology, Yale University, New Haven, CT, USA

    Kevan C. Herold & Noah Biru

  2. Department of Internal Medicine, Yale University, New Haven, CT, USA

    Kevan C. Herold & Ana Luisa Perdigoto

  3. Anschutz Medical Campus, University of Colorado, Denver, CO, USA

    Thomas Delong

  4. Internal Medicine, VA Connecticut Healthcare System, West Haven, CT, USA

    Ana Luisa Perdigoto

  5. Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA

    Todd M. Brusko

  6. Institute of Immunity & Transplantation, University College London, London, UK

    Lucy S. K. Walker

  7. Division of Infection & Immunity, University College London, London, UK

    Lucy S. K. Walker

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All authors researched data for the article and wrote and edited the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Kevan C. Herold or Lucy S. K. Walker.

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Competing interests

K.C.H. is a co-inventor on a patent for the use of teplizumab to delay type 1 diabetes and has consulted for Sanofi, Provention Bio, GSK, Abata, Gentibio and Idorsia. He is on the scientific advisory board for Sonoma and NexImmune.

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Herold, K.C., Delong, T., Perdigoto, A.L. et al. The immunology of type 1 diabetes. Nat Rev Immunol (2024). https://doi.org/10.1038/s41577-023-00985-4

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