Journal
CELL DEATH & DISEASE
Volume 11, Issue 8, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41419-020-02865-4
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Funding
- Josie Robertson Foundation
- Stand Up to Cancer-Innovative Research Grant [SU2C-AACR-IRG11-17]
- Pew Charitable Trusts
- Alfred P. Sloan Foundation
- NIH [R01 AI137168, T32 GM115327-Tan]
- NIH (MSKCC) [P30 CA008748]
- Gabrielle's Angel Foundation
- Pershing Square Sohn Cancer Research Alliance
- Commonwealth Foundation for Cancer Research
- Center for Experimental Therapeutics of Memorial Sloan Kettering Cancer Center
- Ludwig Center at Memorial Sloan Kettering Cancer Center
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Canonical inflammasomes are innate immune signaling platforms that are formed in response to intracellular pathogen-associated signals and trigger caspase-1-dependent pyroptosis. Inflammasome formation and signaling is thought to mainly occur in myeloid cells, and in particular monocytes and macrophages. Here we show that small molecule inhibitors of dipeptidyl peptidases 8 and 9 (DPP8/9), which activate the related CARD8 and NLRP1 inflammasomes, also activate pyroptosis in human and rodent resting lymphocytes. We found that both CD4(+) and CD8(+) T cells were particularly sensitive to these inhibitors, although the sensitivity of T cells, like macrophages, varied considerably between species. In human T cells, we show that CARD8 mediates DPP8/9 inhibitor-induced pyroptosis. Intriguingly, although activated human T cells express the key proteins known to be required for CARD8-mediated pyroptosis, these cells were completely resistant to DPP8/9 inhibitors. Overall, these data show that resting lymphoid cells can activate at least one inflammasome, revealing additional cell types and states poised to undergo rapid pyroptotic cell death in response to danger-associated signals.
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