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Soluble FAS ligand is not required for pancreatic islet inflammation or beta-cell destruction in non-obese diabetic mice

CD8(+) T cells play a central role in beta-cell destruction in type 1 diabetes. CD8(+) T cells use two main effector pathways to kill target cells, perforin plus granzymes and FAS ligand (FASL). We and others have established that in non-obese diabetic (NOD) mice, perforin is the dominant effector m...

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Autores principales: Trivedi, Prerak M., Fynch, Stacey, Kennedy, Lucy M., Chee, Jonathan, Krishnamurthy, Balasubramanian, O’Reilly, Lorraine A., Strasser, Andreas, Kay, Thomas W. H., Thomas, Helen E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755132/
https://www.ncbi.nlm.nih.gov/pubmed/31552143
http://dx.doi.org/10.1038/s41420-019-0217-z
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author Trivedi, Prerak M.
Fynch, Stacey
Kennedy, Lucy M.
Chee, Jonathan
Krishnamurthy, Balasubramanian
O’Reilly, Lorraine A.
Strasser, Andreas
Kay, Thomas W. H.
Thomas, Helen E.
author_facet Trivedi, Prerak M.
Fynch, Stacey
Kennedy, Lucy M.
Chee, Jonathan
Krishnamurthy, Balasubramanian
O’Reilly, Lorraine A.
Strasser, Andreas
Kay, Thomas W. H.
Thomas, Helen E.
author_sort Trivedi, Prerak M.
collection PubMed
description CD8(+) T cells play a central role in beta-cell destruction in type 1 diabetes. CD8(+) T cells use two main effector pathways to kill target cells, perforin plus granzymes and FAS ligand (FASL). We and others have established that in non-obese diabetic (NOD) mice, perforin is the dominant effector molecule by which autoreactive CD8(+) T cells kill beta cells. However, blocking FASL pharmacologically was shown to protect NOD mice from diabetes, indicating that FASL may have some role. FASL can engage with its receptor FAS on target cells either as membrane bound or soluble FASL. It has been shown that membrane-bound FASL is required to stimulate FAS-induced apoptosis in target cells, whereas excessive soluble FASL can induce NF-κB-dependent gene expression and inflammation. Because islet inflammation is a feature of autoimmune diabetes, we tested whether soluble FASL could be important in disease pathogenesis independent of its cell death function. We generated NOD mice deficient in soluble FASL, while maintaining expression of membrane-bound FASL due to a mutation in the FASL sequence required for cleavage by metalloproteinase. NOD mice lacking soluble FASL had normal numbers of lymphocytes in their spleen and thymus. Soluble FASL deficient NOD mice had similar islet inflammation as wild-type NOD mice and were not protected from diabetes. Our data indicate that soluble FASL is not required in development of autoimmune diabetes.
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spelling pubmed-67551322019-09-24 Soluble FAS ligand is not required for pancreatic islet inflammation or beta-cell destruction in non-obese diabetic mice Trivedi, Prerak M. Fynch, Stacey Kennedy, Lucy M. Chee, Jonathan Krishnamurthy, Balasubramanian O’Reilly, Lorraine A. Strasser, Andreas Kay, Thomas W. H. Thomas, Helen E. Cell Death Discov Article CD8(+) T cells play a central role in beta-cell destruction in type 1 diabetes. CD8(+) T cells use two main effector pathways to kill target cells, perforin plus granzymes and FAS ligand (FASL). We and others have established that in non-obese diabetic (NOD) mice, perforin is the dominant effector molecule by which autoreactive CD8(+) T cells kill beta cells. However, blocking FASL pharmacologically was shown to protect NOD mice from diabetes, indicating that FASL may have some role. FASL can engage with its receptor FAS on target cells either as membrane bound or soluble FASL. It has been shown that membrane-bound FASL is required to stimulate FAS-induced apoptosis in target cells, whereas excessive soluble FASL can induce NF-κB-dependent gene expression and inflammation. Because islet inflammation is a feature of autoimmune diabetes, we tested whether soluble FASL could be important in disease pathogenesis independent of its cell death function. We generated NOD mice deficient in soluble FASL, while maintaining expression of membrane-bound FASL due to a mutation in the FASL sequence required for cleavage by metalloproteinase. NOD mice lacking soluble FASL had normal numbers of lymphocytes in their spleen and thymus. Soluble FASL deficient NOD mice had similar islet inflammation as wild-type NOD mice and were not protected from diabetes. Our data indicate that soluble FASL is not required in development of autoimmune diabetes. Nature Publishing Group UK 2019-09-23 /pmc/articles/PMC6755132/ /pubmed/31552143 http://dx.doi.org/10.1038/s41420-019-0217-z Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Trivedi, Prerak M.
Fynch, Stacey
Kennedy, Lucy M.
Chee, Jonathan
Krishnamurthy, Balasubramanian
O’Reilly, Lorraine A.
Strasser, Andreas
Kay, Thomas W. H.
Thomas, Helen E.
Soluble FAS ligand is not required for pancreatic islet inflammation or beta-cell destruction in non-obese diabetic mice
title Soluble FAS ligand is not required for pancreatic islet inflammation or beta-cell destruction in non-obese diabetic mice
title_full Soluble FAS ligand is not required for pancreatic islet inflammation or beta-cell destruction in non-obese diabetic mice
title_fullStr Soluble FAS ligand is not required for pancreatic islet inflammation or beta-cell destruction in non-obese diabetic mice
title_full_unstemmed Soluble FAS ligand is not required for pancreatic islet inflammation or beta-cell destruction in non-obese diabetic mice
title_short Soluble FAS ligand is not required for pancreatic islet inflammation or beta-cell destruction in non-obese diabetic mice
title_sort soluble fas ligand is not required for pancreatic islet inflammation or beta-cell destruction in non-obese diabetic mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755132/
https://www.ncbi.nlm.nih.gov/pubmed/31552143
http://dx.doi.org/10.1038/s41420-019-0217-z
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