DPP8/9 inhibitors activate the CARD8 inflammasome in resting lymphocytes

Cell Death Dis. 2020 Aug 14;11(8):628. doi: 10.1038/s41419-020-02865-4.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • CARD Signaling Adaptor Proteins / metabolism*
  • Cell Cycle* / drug effects
  • Cells, Cultured
  • Dipeptidases / antagonists & inhibitors*
  • Dipeptidases / metabolism
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / antagonists & inhibitors*
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / metabolism
  • Humans
  • Inflammasomes / metabolism*
  • Lymphocyte Activation / drug effects
  • Lymphocytes / drug effects
  • Lymphocytes / metabolism*
  • Mice
  • NLR Proteins
  • Neoplasm Proteins / metabolism*
  • Protease Inhibitors / pharmacology
  • Pyroptosis / drug effects
  • Rats


  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • CARD8 protein, human
  • Inflammasomes
  • NLR Proteins
  • NLRP1 protein, human
  • Neoplasm Proteins
  • Protease Inhibitors
  • Dipeptidases
  • DPP9 protein, human
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
  • DPP8 protein, human