. 2019 Apr; 1461(1):73-103.
doi: 10.1111/nyas.14106.

Type 1 diabetes pathogenesis and the role of inhibitory receptors in islet tolerance

Tijana Martinov 1 Brian T Fife 1 
  • PMID: 31025378
  •     397 References
  •     5 citations


Type 1 diabetes (T1D) affects over a million Americans, and disease incidence is on the rise. Despite decades of research, there is still no cure for this disease. Exciting beta cell replacement strategies are being developed, but in order for such approaches to work, targeted immunotherapies must be designed. To selectively halt the autoimmune response, researchers must first understand how this response is regulated and which tolerance checkpoints fail during T1D development. Herein, we discuss the current understanding of T1D pathogenesis in humans, genetic and environmental risk factors, presumed roles of CD4+ and CD8+ T cells as well as B cells, and implicated autoantigens. We also highlight studies in non-obese diabetic mice that have demonstrated the requirement for CD4+ and CD8+ T cells and B cells in driving T1D pathology. We present an overview of central and peripheral tolerance mechanisms and comment on existing controversies in the field regarding central tolerance. Finally, we discuss T cell- and B cell-intrinsic tolerance mechanisms, with an emphasis on the roles of inhibitory receptors in maintaining islet tolerance in humans and in diabetes-prone mice, and strategies employed to date to harness inhibitory receptor signaling to prevent or reverse T1D.

Keywords: cytotoxic T lymphocyte-associated protein-4; lymphocyte activation gene-3; non-obese diabetic mice; programmed death-1; tolerance; type 1 diabetes.

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CTLA-4 blockade increases IFNgamma-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients.
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Maarit Oikarinen, Sisko Tauriainen, +6 authors, Heikki Hyöty.
Diabetes, 2012 Feb 09; 61(3). PMID: 22315304    Free PMC article.
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Creg J Workman, Dario A A Vignali.
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Tolerance through indifference: autoreactive B cells to the nuclear antigen La show no evidence of tolerance in a transgenic model.
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J Immunol, 2003 Nov 25; 171(11). PMID: 14634099
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Henry Erlich, Ana Maria Valdes, +11 authors, Type 1 Diabetes Genetics Consortium.
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Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3.
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Cell, 2018 Dec 26; 176(1-2). PMID: 30580966    Free PMC article.
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Beatriz León, André Ballesteros-Tato, Troy D Randall, Frances E Lund.
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Genetic evidence that the differential expression of the ligand-independent isoform of CTLA-4 is the molecular basis of the Idd5.1 type 1 diabetes region in nonobese diabetic mice.
Manabu Araki, Denise Chung, +11 authors, Linda S Wicker.
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R Quartey-Papafio, T Lund, +7 authors, E Simpson.
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Mechanisms of Regulatory B cell Function in Autoimmune and Inflammatory Diseases beyond IL-10.
Avijit Ray, Bonnie N Dittel.
J Clin Med, 2017 Jan 27; 6(1). PMID: 28124981    Free PMC article.
BCG-Induced Cross-Protection and Development of Trained Immunity: Implication for Vaccine Design.
Camila Covián, Ayleen Fernández-Fierro, +7 authors, Alexis M Kalergis.
Front Immunol, 2019 Dec 19; 10. PMID: 31849980    Free PMC article.
Highly Cited. Review.
Pancreatic β-cells in type 1 and type 2 diabetes mellitus: different pathways to failure.
Décio L Eizirik, Lorenzo Pasquali, Miriam Cnop.
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From Mesenchymal Stromal/Stem Cells to Insulin-Producing Cells: Immunological Considerations.
Ayman F Refaie, Batoul L Elbassiouny, +5 authors, Mohamed A Ghoneim.
Front Immunol, 2021 Jul 13; 12. PMID: 34248981    Free PMC article.
The Role of Programmed Death-1 in Type 1 Diabetes.
Christopher G Tucker, Alexander J Dwyer, Brian T Fife, Tijana Martinov.
Curr Diab Rep, 2021 May 07; 21(6). PMID: 33956235    Free PMC article.
From Pancreatic β-Cell Gene Networks to Novel Therapies for Type 1 Diabetes.
Decio L Eizirik, Florian Szymczak, Maria Inês Alvelos, Frank Martin.
Diabetes, 2021 Aug 22; 70(9). PMID: 34417266    Free PMC article.