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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...

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Autores principales: Reed, Brendan, Crawford, Frances, Hill, Ryan C., Jin, Niyun, White, Janice, Krovi, S. Harsha, Marrack, Philippa, Hansen, Kirk, Kappler, John W.
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
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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.
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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
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