Cargando…
Lysosomal cathepsin creates chimeric epitopes for diabetogenic CD4 T cells via transpeptidation
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 com...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590512/ https://www.ncbi.nlm.nih.gov/pubmed/33095259 http://dx.doi.org/10.1084/jem.20192135 |
_version_ | 1783600816666443776 |
---|---|
author | Reed, Brendan Crawford, Frances Hill, Ryan C. Jin, Niyun White, Janice Krovi, S. Harsha Marrack, Philippa Hansen, Kirk Kappler, John W. |
author_facet | Reed, Brendan Crawford, Frances Hill, Ryan C. Jin, Niyun White, Janice Krovi, S. Harsha Marrack, Philippa Hansen, Kirk Kappler, John W. |
author_sort | Reed, Brendan |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7590512 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-75905122020-11-03 Lysosomal cathepsin creates chimeric epitopes for diabetogenic CD4 T cells via transpeptidation Reed, Brendan Crawford, Frances Hill, Ryan C. Jin, Niyun White, Janice Krovi, S. Harsha Marrack, Philippa Hansen, Kirk Kappler, John W. J Exp Med Article 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. Rockefeller University Press 2020-10-23 /pmc/articles/PMC7590512/ /pubmed/33095259 http://dx.doi.org/10.1084/jem.20192135 Text en © 2020 Reed et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Reed, Brendan Crawford, Frances Hill, Ryan C. Jin, Niyun White, Janice Krovi, S. Harsha Marrack, Philippa Hansen, Kirk Kappler, John W. Lysosomal cathepsin creates chimeric epitopes for diabetogenic CD4 T cells via transpeptidation |
title | Lysosomal cathepsin creates chimeric epitopes for diabetogenic CD4 T cells via transpeptidation |
title_full | Lysosomal cathepsin creates chimeric epitopes for diabetogenic CD4 T cells via transpeptidation |
title_fullStr | Lysosomal cathepsin creates chimeric epitopes for diabetogenic CD4 T cells via transpeptidation |
title_full_unstemmed | Lysosomal cathepsin creates chimeric epitopes for diabetogenic CD4 T cells via transpeptidation |
title_short | Lysosomal cathepsin creates chimeric epitopes for diabetogenic CD4 T cells via transpeptidation |
title_sort | lysosomal cathepsin creates chimeric epitopes for diabetogenic cd4 t cells via transpeptidation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590512/ https://www.ncbi.nlm.nih.gov/pubmed/33095259 http://dx.doi.org/10.1084/jem.20192135 |
work_keys_str_mv | AT reedbrendan lysosomalcathepsincreateschimericepitopesfordiabetogeniccd4tcellsviatranspeptidation AT crawfordfrances lysosomalcathepsincreateschimericepitopesfordiabetogeniccd4tcellsviatranspeptidation AT hillryanc lysosomalcathepsincreateschimericepitopesfordiabetogeniccd4tcellsviatranspeptidation AT jinniyun lysosomalcathepsincreateschimericepitopesfordiabetogeniccd4tcellsviatranspeptidation AT whitejanice lysosomalcathepsincreateschimericepitopesfordiabetogeniccd4tcellsviatranspeptidation AT krovisharsha lysosomalcathepsincreateschimericepitopesfordiabetogeniccd4tcellsviatranspeptidation AT marrackphilippa lysosomalcathepsincreateschimericepitopesfordiabetogeniccd4tcellsviatranspeptidation AT hansenkirk lysosomalcathepsincreateschimericepitopesfordiabetogeniccd4tcellsviatranspeptidation AT kapplerjohnw lysosomalcathepsincreateschimericepitopesfordiabetogeniccd4tcellsviatranspeptidation |