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

Abstract

Interleukin-1 beta (IL-1{beta}) 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-1{beta} 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-1{beta} 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-1{beta} secretion. Also, caspase-1 rather than caspase-8 cleaves pro-IL-1{beta} in human myeloid cells. This process depends on TNF-, CD40L and IFN-{gamma} together rather than TNF- alone, leading to upregulated pro-IL-1{beta} expression in human myeloid cells. We additionally show that TNF-, CD40L and IFN-{gamma} independently enhance IL-1{beta} secretion. Together, our study highlights that, despite the shared biology in T-cell-instructed IL-1{beta} production between humans and mice, different underlying molecular pathways are implicated. SummaryLike murine cells, human T-cells stimulate IL-1{beta} secretion from myeloid cells. However, the underlying mechanisms differ, with IL-1{beta} production in humans being driven by TNF-, CD40L, IFN-{gamma}, and Caspase-1, whereas in mice, it is primarily regulated by TNF- and Caspase-8.