Abstract |
The identification of the peptide epitopes presented by major histocompatibility complex class II (MHCII) molecules that drive the CD4 T cell component of autoimmune diseases has presented a formidable challenge over several decades. In type 1 diabetes (T1D), recent insight into this problem has come from the realization that several of the important epitopes are not directly processed from a protein source, but rather pieced together by fusion of different peptide fragments of secretory granule proteins to create new chimeric epitopes. We have proposed that this fusion is performed by a reverse proteolysis reaction called transpeptidation, occurring during the catabolic turnover of pancreatic proteins when secretory granules fuse with lysosomes (crinophagy). Here, we demonstrate several highly antigenic chimeric epitopes for diabetogenic CD4 T cells that are produced by digestion of the appropriate inactive fragments of the granule proteins with the lysosomal protease cathepsin L (Cat-L). This pathway has implications for how self-tolerance can be broken peripherally in T1D and other autoimmune diseases.
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Authors | Brendan Reed, Frances Crawford, Ryan C Hill, Niyun Jin, Janice White, S Harsha Krovi, Philippa Marrack, Kirk Hansen, John W Kappler |
Journal | The Journal of experimental medicine
(J Exp Med)
Vol. 218
Issue 2
(02 01 2021)
ISSN: 1540-9538 [Electronic] United States |
PMID | 33095259
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | © 2020 Reed et al. |
Chemical References |
- Epitopes, T-Lymphocyte
- Histocompatibility Antigens Class II
- Peptide Fragments
- Cathepsins
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Topics |
- Animals
- Autoimmune Diseases
(immunology)
- CD4-Positive T-Lymphocytes
(immunology)
- Cathepsins
(immunology)
- Cell Line
- Diabetes Mellitus, Type 1
(immunology)
- Epitopes, T-Lymphocyte
(immunology)
- Histocompatibility Antigens Class II
(immunology)
- Immune Tolerance
(immunology)
- Lysosomes
(immunology)
- Pancreas
(immunology)
- Peptide Fragments
(immunology)
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