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Deciphering the Pathogenesis of Human Type 1 Diabetes (T1D) by Interrogating T Cells from the “Scene of the Crime”

  • Pathogenesis of Type 1 Diabetes (A Pugliese, Section Editor)
  • Published:
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Abstract

Purpose of Review

Autoimmune-mediated destruction of insulin-producing β-cells within the pancreas results in type 1 diabetes (T1D), which is not yet preventable or curable. Previously, our understanding of the β-cell specific T cell repertoire was based on studies of autoreactive T cell responses in the peripheral blood of patients at risk for, or with, T1D; more recently, investigations have included immunohistochemical analysis of some T cell specificities in the pancreas from organ donors with T1D. Now, we are able to examine live, islet-infiltrating T cells from donors with T1D.

Recent Findings

Analysis of the T cell repertoire isolated directly from the pancreatic islets of donors with T1D revealed pro-inflammatory T cells with targets of known autoantigens, including proinsulin and glutamic acid decarboxylase, as well as modified autoantigens.

Summary

We have assayed the islet-infiltrating T cell repertoire for autoreactivity and function directly from the inflamed islets of T1D organ donors. Design of durable treatments for prevention of or therapy for T1D requires understanding this repertoire.

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Acknowledgments

This research was performed with the support of the Network for Pancreatic Organ Donors with Diabetes (nPOD), a collaborative type 1 diabetes research project sponsored by the Juvenile Diabetes Research Foundation. Organ Procurement Organizations (OPO) partnering with nPOD to provide research resources are listed at http://www.jdrfnpod.org/for-partners/npod-partners/. We thank the families of the donors. We acknowledge the support of the Tom Mandel Islet Transplantation Program and the Australian Islet Transplantation Consortium. We thank Dr. Alvin C. Powers (Vanderbilt University) and Drs. Mark A. Atkinson and Clayton Mathews (University of Florida, Gainesville). We thank Dr. M. Nakayama (Barbara Davis Center for Childhood Diabetes, University of Colorado), Professor Tom Kay, and Associate Professor Helen Thomas (St. Vincent’s Institute of Medical Research, Melbourne, Australia).

The following funding sources supported this research: the Helmsley Charitable Trust 2015PG-T1D057 (SCK), National Institutes of Health/National Institute of Allergy and Infectious Diseases AI126189 (SCK), and the Human Islet Research Network (HIRN) Opportunity Pool Fund National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases U01 DK104162 (SCK), R01 DK108868 (AWM), DP3 DK110845 (AWM), and UC4 DK104223 (AWM), The Australian National Health and Medical Research Council (NHMRC) GNT1123586 (SIM), Diabetes Australia Research Program Y17M1-MANS (SIM) JDRF, America Diabetes Association, 1-15-ACE-14 (SIM) and JDRF 5-CDA-2014-210-A-N (SIM), and Juvenile Diabetes Research Foundation Postdoctoral Fellowship 3-PDF-201703740A-N (JABB).

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Authors and Affiliations

  1. Department of Medicine, Division of Diabetes, Diabetes Center of Excellence, ASC7-2041, University of Massachusetts Medical School, Worcester, MA, 01605, USA

    Sally C. Kent & Jenny Aurielle B. Babon

  2. Immunology and Diabetes Unit, St. Vincent’s Institute of Medical Research, 9 Princes Street, Fitzroy, Victoria, 3065, Australia

    Stuart I. Mannering

  3. Department of Medicine, University of Melbourne, St. Vincent’s Hospital, Fitzroy, Victoria, 3065, Australia

    Stuart I. Mannering

  4. Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, USA

    Aaron W. Michels

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  1. Sally C. Kent
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Correspondence to Sally C. Kent.

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Conflicts of Interest

Sally C. Kent, Jenny Aurielle B. Babon, and Stuart I. Mannering declare that they have no conflict of interest.

Aaron W. Michels reports conflicts outside the submitted work, including a patent Compounds That Modulate Autoimmunity and Methods of Using the Same licensed to ImmunoMolecular Therapeutics, a patent Methods of Preventing and Treating Autoimmunity licensed to ImmunoMolecular Therapeutics, and a patent Insulin Mimotopes and Methods of Using the Same pending. He is the scientific founder and owns shares in ImmunoMolecular Therapeutics, LLC.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of each institutional review board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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This article is part of the Topical Collection on Pathogenesis of Type 1 Diabetes

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Kent, S.C., Mannering, S.I., Michels, A.W. et al. Deciphering the Pathogenesis of Human Type 1 Diabetes (T1D) by Interrogating T Cells from the “Scene of the Crime”. Curr Diab Rep 17, 95 (2017). https://doi.org/10.1007/s11892-017-0915-y

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