The adaptor protein ASC controls transplantation outcomes independently of the inflammasome (TRAN1P.951)

Abstract

Abstract The adaptor protein ASC is known to facilitate caspase-1 activation essential for innate host immunity via the formation of the inflammasome complex - a multi-protein structure responsible for processing IL-1b and IL-18 to their active moieties. Here we report for the first time, a unique inflammasome-independent role for ASC in the control of transplant outcome following allogeneic bone marrow transplantation (BMT). We demonstrate that ASC-deficient donor CD8+ T cells fail to induce GVHD lethality due to an inability to differentiate into fully cytolytic effectors after BMT, with a developmental bias instead towards CD127+KLRG1- memory CD8+ T cells. Despite this, graft-versus-leukaemia effects against BCR-ABL NUP98/HOXA9 primary leukemia remained largely intact. This phenomenon was inflammasome independent, since GVHD lethality and T cell differentiation were not altered in recipients of caspase-1-deficient T cells. We also confirmed a reduced capacity for human T cells in which ASC was knocked down by shRNA to induce xenogeneic GVHD. In a model of bone marrow rejection, ASC expression in recipient CD8+ T cells profoundly impaired graft rejection and was permissive of robust engraftment across MHC barriers and long term survival. Taken together, these findings demonstrate an inflammasome-independent role for ASC in controlling GVHD and graft rejection. Thus, the inhibition of ASC in the clinic represents an important new therapeutic target to manipulate transplant outcomes.