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


Trivedi, PM; Fynch, S; Kennedy, LM; Chee, J; Krishnamurthy, B; O'Reilly, LA; Strasser, A; Kay, TWH; Thomas, HE
2019
Cell Death Discovery
Journal Article
5
136
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-kappaB-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.
Springer Nature
Blood Cells and Blood Cancer
10.1038/s41420-019-0217-z
31552143
Refer to article for additional funding acknowledgements
Refer to copyright notice on published article.

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Creation Date 2019-10-23 02:22:55 Last Modified 2019-10-23 02:50:48