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Title: N-terminal additions to the WE14 peptide of chromogranin A create strong autoantigen agonists in type 1 diabetes

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America
 [1];  [2];  [3];  [2];  [4];  [5];  [6]
  1. Howard Hughes Medical Inst., Denver, CO (United States); National Jewish Health, Denver, CO (United States); Univ. of Colorado, Aurora, CO (United States)
  2. National Jewish Health, Denver, CO (United States)
  3. Howard Hughes Medical Inst., Denver, CO (United States); National Jewish Health, Denver, CO (United States)
  4. Howard Hughes Medical Inst., Denver, CO (United States); National Jewish Health, Denver, CO (United States); Univ. of Colorado School of Medicine, Aurora, CO (United States)
  5. National Jewish Health, Denver, CO (United States); Univ. of Colorado School of Medicine, Aurora, CO (United States)
  6. Howard Hughes Medical Inst., Denver, CO (United States); National Jewish Health, Denver, CO (United States); Univ. of Colorado, Aurora, CO (United States); Univ. of Colorado School of Medicine, Aurora, CO (United States)
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Chromogranin A (ChgA) is an autoantigen for CD4+T cells in the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D). The natural ChgA-processed peptide, WE14, is a weak agonist for the prototypical T cell, BDC-2.5, and other ChgA-specific T-cell clones. Mimotope peptides with much higher activity share a C-terminal motif, WXRM(D/E), that is predicted to lie in the p5 to p9 position in the mouse MHC class II, IAg7binding groove. This motif is also present in WE14 (WSRMD), but at its N terminus. Therefore, to place the WE14 motif into the same position as seen in the mimotopes, we added the amino acids RLGL to its N terminus. Like the other mimotopes, RLGL-WE14, is much more potent than WE14 in T-cell stimulation and activates a diverse population of CD4+T cells, which also respond to WE14 as well as islets from WT, but not ChgA–/–mice. The crystal structure of the IAg7–RLGL–WE14 complex confirmed the predicted placement of the peptide within the IAg7groove. Fluorescent IAg7–RLGL–WE14 tetramers bind to ChgA-specific T-cell clones and easily detect ChgA-specific T cells in the pancreas and pancreatic lymph nodes of NOD mice. Here, the prediction that many different N-terminal amino acid extensions to the WXRM(D/E) motif are sufficient to greatly improve T-cell stimulation leads us to propose that such a posttranslational modification may occur uniquely in the pancreas or pancreatic lymph nodes, perhaps via the mechanism of transpeptidation. This modification could account for the escape of these T cells from thymic negative selection.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
National Inst. of General Medical Sciences from the National Inst. of Health; NIH Office of Research Infrastructure Programs High-End Instrumentation Grant; Boettcher Foundation
Grant/Contract Number:
P41 GM103403; S10 RR029205; AI-18785; CCTSI KL2 TR001080; ES025797
OSTI ID:
1225747
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, Issue 43; ISSN 0027-8424
Publisher:
National Academy of SciencesCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 34 works
Citation information provided by
Web of Science

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Cited By (12)

Chromogranin A and its fragments in cardiovascular, immunometabolic, and cancer regulation journal October 2019
Increased Effector Memory Insulin-Specific CD4+ T Cells Correlate With Insulin Autoantibodies in Patients With Recent-Onset Type 1 Diabetes journal August 2017
A biomimetic five-module chimeric antigen receptor ( 5M CAR) designed to target and eliminate antigen-specific T cells journal January 2020
C-terminal modification of the insulin B:11–23 peptide creates superagonists in mouse and human type 1 diabetes journal December 2017
T Cell-Mediated Beta Cell Destruction: Autoimmunity and Alloimmunity in the Context of Type 1 Diabetes journal December 2017
HLA variation and disease journal January 2018
Catestatin as a Target for Treatment of Inflammatory Diseases journal October 2018
Chromogranin A Regulation of Obesity and Peripheral Insulin Sensitivity journal February 2017
Adaptive Immunity Is the Key to the Understanding of Autoimmune and Paraneoplastic Inflammatory Central Nervous System Disorders journal March 2017
A biomimetic five-module chimeric antigen receptor ( 5M CAR) designed to target and eliminate antigen-specific T cells journal November 2020
Next-generation regulatory T cell therapy journal September 2019
How C-terminal additions to insulin B-chain fragments create superagonists for T cells in mouse and human type 1 diabetes journal April 2019

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
autoimmunity
antigen processing
posttranslational
modification
crystallography
transpeptidation