Pancreatic islets communicate with lymphoid tissues via exocytosis of insulin peptides

Xiaoxiao Wan, Bernd H. Zinselmeyer, Pavel N. Zakharov, Anthony N. Vomund, Ruth Taniguchi, Laura Santambrogio, Mark S. Anderson, Cheryl F. Lichti, Emil R. Unanue

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31 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)107-111
Number of pages5
JournalNature
Volume560
Issue number7716
DOIs
StatePublished - Aug 2 2018

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    Wan, X., Zinselmeyer, B. H., Zakharov, P. N., Vomund, A. N., Taniguchi, R., Santambrogio, L., Anderson, M. S., Lichti, C. F., & Unanue, E. R. (2018). Pancreatic islets communicate with lymphoid tissues via exocytosis of insulin peptides. Nature, 560(7716), 107-111. https://doi.org/10.1038/s41586-018-0341-6