Distinct mechanisms are employed by T-cell-instructed myeloid cells for IL-1β production in humans and mice

Interleukin-1 beta (IL-1β) is known as an inflammasome-dependent pro-inflammatory cytokine that has been implicated in T-cell-driven autoimmune diseases. In mice, T-cells were reported to instruct myeloid cells to produce IL-1β via an inflammasome-independent mechanism, that engages TNFR and Fas-caspase-8-dependent signalling pathways. In this study, we explored T-cell-driven myeloid IL-1β production in humans. Co-culturing of autologous primary T-cells (memory CD4+ and CD8+) with myeloid cells (monocyte, macrophage and dendritic cells) revealed that both memory CD4+ and CD8+ T cells induce IL-1β secretion. Also, caspase-1 rather than caspase-8 cleaves pro-IL-1β in human myeloid cells. This process depends on TNF-α, CD40L and IFN-γ together rather than TNF-α alone, leading to upregulated pro-IL-1β expression in human myeloid cells. We additionally show that TNF-α, CD40L and IFN-γ independently enhance IL-1β secretion. Together, our study highlights that, despite the shared biology in T-cell-instructed IL-1β production between humans and mice, different underlying molecular pathways are implicated.