T cells instruct myeloid cells to produce inflammasome-independent IL-1β and cause autoimmunity

Abstract

The cytokine interleukin (IL)-1 beta is a key mediator of antimicrobial immunity as well as autoimmune inflammation. Production of IL-1 beta requires transcription by innate immune receptor signaling and maturational cleavage by inflammasomes. Whether this mechanism applies to IL-1 beta production seen in T cell-driven autoimmune diseases remains unclear. Here, we describe an inflammasome-independent pathway of IL-1 beta production that was triggered upon cognate interactions between effector CD4(+) T cells and mononuclear phagocytes (MPs). The cytokine TNF produced by activated CD4(+) T cells engaged its receptor TNFR on MPs, leading to pro-IL-1 beta synthesis. Membrane-bound FasL, expressed by CD4(+) T cells, activated death receptor Fas signaling in MPs, resulting in caspase-8-dependent pro-IL-1 beta cleavage. The T cell-instructed IL-1 beta resulted in systemic inflammation, whereas absence of TNFR or Fas signaling protected mice from CD4(+) Tcell-driven autoimmunity. The TNFR-Fas-caspase-8-dependent pathway provides a mechanistic explanation for IL-1 beta production and its consequences in CD4(+) T cell-driven autoimmune pathology.