N-terminal additions to the WE14 peptide of chromogranin A create strong autoantigen agonists in type 1 diabetes
- Howard Hughes Medical Inst., Denver, CO (United States); National Jewish Health, Denver, CO (United States); Univ. of Colorado, Aurora, CO (United States)
- National Jewish Health, Denver, CO (United States)
- Howard Hughes Medical Inst., Denver, CO (United States); National Jewish Health, Denver, CO (United States)
- 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)
- National Jewish Health, Denver, CO (United States); Univ. of Colorado School of Medicine, Aurora, CO (United States)
- 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)
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
Web of Science
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