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Nature. 2018 Aug;560(7716):107-111. doi: 10.1038/s41586-018-0341-6. Epub 2018 Jul 18.

Pancreatic islets communicate with lymphoid tissues via exocytosis of insulin peptides.

Author information

1
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
2
Diabetes Center, University of California, San Francisco, San Francisco, CA, USA.
3
Department of Pathology, Albert Einstein College of Medicine, New York, NY, USA.
4
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. unanue@wustl.edu.

Abstract

Tissue-specific autoimmunity occurs when selected antigens presented by susceptible alleles of the major histocompatibility complex are recognized by T cells. However, the reason why certain specific self-antigens dominate the response and are indispensable for triggering autoreactivity is unclear. Spontaneous presentation of insulin is essential for initiating autoimmune type 1 diabetes in non-obese diabetic mice1,2. A major set of pathogenic CD4 T cells specifically recognizes the 12-20 segment of the insulin B-chain (B:12-20), an epitope that is generated from direct presentation of insulin peptides by antigen-presenting cells3,4. These T cells do not respond to antigen-presenting cells that have taken up insulin that, after processing, leads to presentation of a different segment representing a one-residue shift, B:13-214. CD4 T cells that recognize B:12-20 escape negative selection in the thymus and cause diabetes, whereas those that recognize B:13-21 have only a minor role in autoimmunity3-5. Although presentation of B:12-20 is evident in the islets3,6, insulin-specific germinal centres can be formed in various lymphoid tissues, suggesting that insulin presentation is widespread7,8. Here we use live imaging to document the distribution of insulin recognition by CD4 T cells throughout various lymph nodes. Furthermore, we identify catabolized insulin peptide fragments containing defined pathogenic epitopes in β-cell granules from mice and humans. Upon glucose challenge, these fragments are released into the circulation and are recognized by CD4 T cells, leading to an activation state that results in transcriptional reprogramming and enhanced diabetogenicity. Therefore, a tissue such as pancreatic islets, by releasing catabolized products, imposes a constant threat to self-tolerance. These findings reveal a self-recognition pathway underlying a primary autoantigen and provide a foundation for assessing antigenic targets that precipitate pathogenic outcomes by systemically sensitizing lymphoid tissues.

PMID:
30022165
PMCID:
PMC6090537
DOI:
10.1038/s41586-018-0341-6
[Indexed for MEDLINE]
Free PMC Article

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