CARD8 inflammasome activation triggers pyroptosis in human T cells

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Inflammasomes are multiprotein complexes that mediate inflammatory responses and programmed cell death.
• Pyroptosis is a highly inflammatory form of cell death executed by inflammasomes, primarily characterized in myeloid cells.
• Gasdermin D (GSDMD) cleavage by caspase-1 is a critical step in pyroptosis, leading to plasma membrane pore formation.

Purpose of the Study:

• To investigate the role of CARD8 inflammasome sensor in T cells.
• To determine if dipeptidyl-peptidase (DPP) inhibition can trigger pyroptosis in primary human T cells.
• To elucidate the molecular mechanisms underlying CARD8-mediated pyroptosis in T cells.

Main Methods:

• Primary human CD4 and CD8 T cells were treated with Val-boroPro, a dipeptidyl-peptidase inhibitor.
• Morphological and biochemical analyses were performed to characterize the cell death.
• Genetic approaches were used to dissect the CARD8-caspase-1-GSDMD signaling axis.
• The role of DPP9 in regulating CARD8 activation was investigated.

Main Results:

• Blocking DPPs with Val-boroPro induced pyroptosis in primary human CD4 and CD8 T cells.
• This T cell pyroptosis was dependent on the CARD8-caspase-1-GSDMD pathway.
• DPP9 was identified as the specific DPP that restrains CARD8 activation.
• CARD8-induced pyroptosis was observed in resting T cells but not in activated T cells.

Conclusions:

• Inflammasome signaling and pyroptosis are relevant to T cells, extending beyond myeloid cells.
• The CARD8-caspase-1-GSDMD axis represents a novel pathway for pyroptosis induction in T cells.
• DPP inhibition offers a potential strategy to modulate T cell pyroptosis, with implications for adaptive immunity.