Inflammasome activation occurs in CD4+ and CD8+ T cells during graft-versus-host disease

Abstract

A severe complication of hematopoietic stem cell transplantation is graft-versus-host disease (GvHD), a reaction that occurs following the transfer of donor immune cells (the graft) into an allogeneic host. Transplanted cells recognize host alloantigens as foreign, resulting in the activation of donor T cells and migration of these pathological cells into host tissues. In this study, we found that caspase-1 is activated in alloreactive murine and human CD4+ and CD8+ T cells early during acute GvHD (aGvHD). The presence of inflammasome-bound active caspase-1 (p33) and ASC-speck formation confirmed inflammasome activation in these cells. We further measured gasdermin D (GSDMD) cleavage and IL-18 secretion from alloreactive T cells ex vivo. Isolated T cells with high levels of active caspase-1 had a strong inflammatory transcriptional signature and a metabolic phenotype similar to inflammatory myeloid cells, including the upregulation of proinflammatory cytokines and metabolic switch from oxidative phosphorylation to aerobic glycolysis. We also observed oxidative stress, mitochondrial dysfunction, and cell death phenotypes consistent with inflammatory cell death in alloreactive T cells. For the first time, this study characterizes caspase-1 activation in transplanted T cells during aGvHD, using mouse and human models, adding to a body of literature supporting inflammasome function in cells of the adaptive immune system.

Sex-dependent effects of carbohydrate source and quantity on caspase-1 activity in the mouse central nervous system

“…To evaluate how changes in diet influence inflammasome activation in the central nervous system (CNS), we utilized mice expressing a caspase-1 biosensor that allows caspase-1 activation to be monitored in vivo [ 47 – 50 ]. These mice express a circularly permuted luciferase that is inactive prior to activation of caspase-1.…”

Human natural killer cells can activate NLRP1 and NLRP3 inflammasomes and drives pyroptosis

“…In this regard, inflammasome biology has been mostly characterized in macrophages, and at least partially studied in other cell types such as endothelial cells, fibroblasts, epithelial cells, and T cells [8][9][10][11]. However, it is unknown if NK cells are equipped with functional inflammasome components, and thus, this could represent an underexplored arm of the diverse immune mechanisms mediated by these cells and an important source of inflammation.…”