[RETRACTED] Hltf-deletion activates an IL33/β cell-CD8+T cell axis that triggers neonatal death v1
Year: 2019
Type: preprint
Abstract: [RETRACTED] Epigenetic silencing of HLTF in human β cells alters insulin secretion and is associated with diabetes. Here we examine the effects of Hltf-deletion on β cell function in genetically engineered mouse models. The developmental timeline for the exclusive expression of full-length Hltf mRNA and protein overlaps with the organization of murine pancreatic islets. Reduced insulin in the pancreatic β cells of global Hltf-deleted near-term (E18.5) fetal mice predicts postpartum hypoinsulinemia. Seventy-five percent of newborn global Hltf-deleted postprandial mice die with negligible serum insulin levels, and their apoptotic β cells are devoid of insulin. They are also hypoglycemic. Newborn β cell-specific Hltf-deleted mice succumb to the same loss of glucose homeostasis indicating the phenotype is solely attributable to loss of β cell function. Confirmation that an intact immune system is an absolute requirement for the phenotype resulted from breeding theHltf-deletion into the Rag2-IL2-null background. Triple null (Hltf-/-Rag2-/-IL2-/-) newborn mice that lack functional receptors for IL-2,-4,-7,-9,-15, and -21, and have severe lymphocyte developmental impairment (deficient T and B cells, no NK cells) are euglycemic and normoinsulinemic with normal survival rates.Transcriptomic profiling (RNA-seq) eliminated β cell-specific Hltf-deletion on gene programs essential for normal development, and β cell secretion. Significantly, Hltf-deletion induced IL33/β cell signaling that promoted islet infiltration of fetal CD8+T cells and β cell apoptosis. Our data suggest Hltf-deleted newborns that are not profoundly hypoglycemic survive in the absence of memory CD8+T cells. These Hltf-deletion studies provide mechanistic insights to how Hltf-deletion in β cells promotes their immune destruction.
Author: Gurvinder Kaur
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4234420125