Title: Small Molecule Binding to Alzheimer Risk Factor CD33 Promotes A beta Phagocytosis
Authors: Miles, LA
Hermans, SJ
Crespi, GAN
Gooi, JH
Doughty, L
Nero, TL
Markulic, J
Ebneth, A
Wroblowski, B
Oehlrich, D
Trabanco, AA
Rives, ML
Royaux, I
Hancock, NC
Parker, MW
Issue Year: 2019
Publisher CELL PRESS
Abstract 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 NE-KB-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.
URI: https://publications.svi.edu.au/publications/7665
Other Identifiers 10.1016/j.isci.2019.07.023
Publication type Article