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

Abstract

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, IA^g7binding 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 IA^g7–RLGL–WE14 complex confirmed the predicted placement of the peptide within the IA^g7groove. Fluorescent IA^g7–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) motifmore » 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.« less

Authors:

Jin, Niyun ^[1]; Wang, Yang ^[2]; Crawford, Frances ^[3]; White, Janice ^[2]; Marrack, Philippa ^[4]; Dai, Shaodong ^[5]; Kappler, John W. ^[6]

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+ Show Author Affiliations

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)

Publication Date:

Fri Oct 09 00:00:00 EDT 2015

Research Org.:

Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Org.:

National Inst. of General Medical Sciences from the National Inst. of Health; NIH Office of Research Infrastructure Programs High-End Instrumentation Grant; Boettcher Foundation

OSTI Identifier:

1225747

Grant/Contract Number:  

P41 GM103403; S10 RR029205; AI-18785; CCTSI KL2 TR001080; ES025797

Resource Type:

Journal Article: Accepted Manuscript

Journal Name:

Proceedings of the National Academy of Sciences of the United States of America

Additional Journal Information:

Journal Volume: 112; Journal Issue: 43; Journal ID: ISSN 0027-8424

Publisher:

National Academy of Sciences

Country of Publication:

United States

Language:

ENGLISH

Subject:

59 BASIC BIOLOGICAL SCIENCES; autoimmunity; antigen processing; posttranslational; modification; crystallography; transpeptidation