TY - JOUR
T1 - Pancreatic islets communicate with lymphoid tissues via exocytosis of insulin peptides
AU - Wan, Xiaoxiao
AU - Zinselmeyer, Bernd H.
AU - Zakharov, Pavel N.
AU - Vomund, Anthony N.
AU - Taniguchi, Ruth
AU - Santambrogio, Laura
AU - Anderson, Mark S.
AU - Lichti, Cheryl F.
AU - Unanue, Emil R.
N1 - Publisher Copyright:
© 2018, Macmillan Publishers Ltd., part of Springer Nature.
PY - 2018/8/2
Y1 - 2018/8/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85050960853&partnerID=8YFLogxK
U2 - 10.1038/s41586-018-0341-6
DO - 10.1038/s41586-018-0341-6
M3 - Article
C2 - 30022165
AN - SCOPUS:85050960853
SN - 0028-0836
VL - 560
SP - 107
EP - 111
JO - Nature
JF - Nature
IS - 7716
ER -