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

Abstract

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 active in alloreactive murine and human CD4 +and CD8 +T cells early during acute GvHD (aGvHD) development. The presence of inflammasome-bound, active caspase-1 (p33) and ASC speck formation confirmed inflammasome activation in these cells. 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 and mitochondrial dysfunction, 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. NIH