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Pancreatic islets communicate with lymphoid tissues via exocytosis of insulin peptides.
- Source :
-
Nature [Nature] 2018 Aug; Vol. 560 (7716), pp. 107-111. Date of Electronic Publication: 2018 Jul 18. - Publication Year :
- 2018
-
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 mice <superscript>1,2</superscript> . 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 <superscript>3,4</superscript> . 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 <superscript>4</superscript> . 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 <superscript>3-5</superscript> . Although presentation of B:12-20 is evident in the islets <superscript>3,6</superscript> , insulin-specific germinal centres can be formed in various lymphoid tissues, suggesting that insulin presentation is widespread <superscript>7,8</superscript> . 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.
- Subjects :
- Adult
Animals
Antigen Presentation immunology
Cytoplasmic Granules chemistry
Cytoplasmic Granules drug effects
Cytoplasmic Granules metabolism
Epitopes immunology
Female
Glucose metabolism
Glucose pharmacology
Humans
Insulin blood
Insulin chemistry
Insulin immunology
Islets of Langerhans drug effects
Lymphoid Tissue cytology
Lymphoid Tissue drug effects
Lymphoid Tissue immunology
Male
Mice, Inbred NOD
Middle Aged
Peptide Fragments blood
Peptide Fragments chemistry
Peptide Fragments immunology
Phenotype
T-Lymphocytes drug effects
T-Lymphocytes immunology
Exocytosis drug effects
Insulin metabolism
Islets of Langerhans cytology
Islets of Langerhans metabolism
Lymphoid Tissue metabolism
Peptide Fragments metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 560
- Issue :
- 7716
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 30022165
- Full Text :
- https://doi.org/10.1038/s41586-018-0341-6