ASC Modulates CTL Cytotoxicity and Transplant Outcome Independent of the Inflammasome

Melody Cheong, Kate H. Gartlan, Jason S. Lee, Siok Keen Tey, Ping Zhang, Rachel D. Kuns, Christopher E. Andoniou, Jose Paulo Martins, Karshing Chang, Vivien R. Sutton, Greg Kelly, Antiopi Varelias, Slavica Vuckovic, Kate A. Markey, Glen M. Boyle, Mark J. Smyth, Christian R. Engwerda, Kelli P.A. MacDonald, Joseph A. Trapani, Mariapia A. Degli-EspostiMotoko Koyama, Geoffrey R. Hill

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The adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) is known to facilitate caspase-1 activation, which is essential for innate host immunity via the formation of the inflammasome complex, a multiprotein structure responsible for processing IL1β and IL18 into their active moieties. Here, we demonstrated that ASC-deficient CD8+ T cells failed to induce severe graft-versus-host disease (GVHD) and had impaired capacity for graft rejection and graft-versus-leukemia (GVL) activity. These effects were inflammasome independent because GVHD lethality was not altered in recipients of caspase-1/11-deficient T cells. We also demonstrated that ASC deficiency resulted in a decrease in cytolytic function, with a reduction in granzyme B secretion and CD107a expression by CD8+ T cells. Altogether, our findings highlight that ASC represents an attractive therapeutic target for improving outcomes of clinical transplantation.

Original languageEnglish
Pages (from-to)1085-1098
Number of pages14
JournalCancer Immunology Research
Issue number8
Publication statusPublished - Aug 2020

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