Pyroptosis-dependent and -independent cross-priming of CD8⁺ T cells by intestinal epithelial cell-derived antigen

The innate immune system detects pathogens and initiates adaptive immune responses. Inflammasomes are central components of the innate immune system, but whether inflammasomes provide sufficient signals to activate adaptive immunity is unclear. In intestinal epithelial cells (IECs), inflammasomes activate a lytic form of cell death called pyroptosis, leading to epithelial cell expulsion and the release of cytokines. Here we employed a genetic system to show that simultaneous antigen expression and inflammasome activation specifically in IECs is sufficient to activate CD8⁺ T cells. By genetic elimination of direct T cell priming by IECs, we found that IEC-derived antigens are cross-presented to CD8⁺ T cells. However, activation of CD8⁺ T cells by IEC-derived antigen only partially depended on IEC pyroptosis. In the absence of inflammasome activation, cross-priming of CD8⁺ T cells required Batf3⁺ dendritic cells (cDC1), whereas cross-priming in the presence of pyroptosis did not. These data suggest the existence of parallel pyroptosis-dependent and pyroptosis-independent but cDC1-dependent pathways for cross-presentation of IEC-derived antigens.