Pluto Bioinformatics

GSE137060: Hltf-deletion activates an IL33/ cell-CD8+T cell axis that triggers neonatal death

Bulk RNA sequencing

Epigenetic silencing of HLTF in human cells alters insulin secretion and is associated with diabetes. Here we examine the effects of Hltf-deletion on 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 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 at a ratio of 3:2 males to females with negligible serum insulin levels, and their apoptotic cells are devoid of insulin. They are also hypoglycemic. Newborn cell-specific Hltf-deleted mice succumb to the same loss of glucose homeostasis indicating the phenotype is solely attributable to loss of cell function. Confirmation that an intact immune system is an absolute requirement for the phenotype resulted from breeding the Hltf-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 cell-specific Hltf-deletion on gene programs essential for normal development, and cell secretion. Significantly, Hltf-deletion induced IL33/ cell signaling that promoted islet infiltration of fetal CD8+T cells and 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 cells promotes their immune destruction. SOURCE: Beverly,S,Chilton (beverly.chilton@ttuhsc.edu) - 5B136 & 137 Texas Tech University HSC