ASC controls T-bet-dependent CTL differentiation and defines transplant outcome independent of the inflammasome. Mus musculus

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-1beta and IL-18 to their active moieties. Here we demonstrate that ASC-deficient CD8+ T cells fail to induce graft-versus-host disease (GVHD) and have impaired capacity for graft rejection and graft-versus-leukemia (GVL) activity. These effects are the result of an inability to differentiate into fully cytolytic, granzyme B-expressing effector cells, with a developmental bias instead towards CD127+KLRG1- memory CD8+ T cells. These alterations in differentiation are inflammasome-independent, since GVHD lethality and CTL differentiation are not altered in recipients of caspase-1-deficient T cells. We demonstrate that ASC binds to T-bet in CD8+ T and in the absence of ASC, the binding of T-bet to the granzyme B promoter is impaired. Thus, the inhibition of ASC represents an attractive therapeutic target to manipulate transplant outcomes. Overall design: Single colour, Illumina MouseRef-8 v2.0 Beadarrays.