Pancreatic islets communicate with lymphoid tissues via exocytosis of insulin peptides

• Published in: Nature (London) 2018-08, Vol.560 (7716), p.107-111
• Main Authors: Wan, Xiaoxiao, Zinselmeyer, Bernd H., Zakharov, Pavel N., Vomund, Anthony N., Taniguchi, Ruth, Santambrogio, Laura, Anderson, Mark S., Lichti, Cheryl F., Unanue, Emil R.
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/31; 14/19; 14/28; 14/34; 14/63; 14/69; 38/90; 38/91; 631/250/21/569; 631/250/249/1313/1418; 631/250/2503; 631/250/38; 64/110; 64/60; 692/699/249/1313/1418; 82/58; 82/75; Adult; Alleles; Animals; Antigen presentation; Antigen Presentation - immunology; Antigen-presenting cells; Antigenic determinants; Antigens; Autoantigens; Autoimmunity; B cells; Beta cells; CD4 antigen; Cell activation; Cell division; Cytoplasmic Granules - chemistry; Cytoplasmic Granules - drug effects; Cytoplasmic Granules - metabolism; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Epitopes; Epitopes - immunology; Exocytosis; Exocytosis - drug effects; Female; Fragments; Germinal centers; Glucose; Glucose - metabolism; Glucose - pharmacology; Haplotypes; Humanities and Social Sciences; Humans; Immune response; Immunological tolerance; Insulin; Insulin - blood; Insulin - chemistry; Insulin - immunology; Insulin - metabolism; Islets of Langerhans - cytology; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Letter; Lymph nodes; Lymphatic system; Lymphocytes; Lymphocytes T; Lymphoid tissue; Lymphoid Tissue - cytology; Lymphoid Tissue - drug effects; Lymphoid Tissue - immunology; Lymphoid Tissue - metabolism; Major histocompatibility complex; Male; Mice; Mice, Inbred NOD; Microscopy; Middle Aged; Motility; multidisciplinary; Negative selection; Obesity; Observations; Pancreas; Peptide Fragments - blood; Peptide Fragments - chemistry; Peptide Fragments - immunology; Peptide Fragments - metabolism; Peptides; Phenotype; Physiological aspects; Properties; Recognition; Resveratrol; Science; Science (multidisciplinary); Self-recognition; Sensitizing; T cell receptors; T cells; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Thymus; Tissues; Transcription; Type 1 diabetes
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-018-0341-6

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 mice 1 , 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 cells 3 , 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:13–21 4 . 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 autoimmunity 3 – 5 . Although presentation of B:12–20 is evident in the islets 3 , 6 , insulin-specific germinal centres can be formed in various lymphoid tissues, suggesting that insulin presentation is widespread 7 , 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. A sensitive T cell tracking assay reveals immunogenic activity of specific catabolized peptide fragments of insulin and their effects on T cell activity in lymph nodes, highlighting communication between pancreatic islets and lymphoid tissue.