PT  - JOURNAL ARTICLE
AU  - Aakanksha Jain
AU  - Ricardo A. Irizarry-Caro
AU  - Amanpreet S. Chawla
AU  - Naomi H. Philip
AU  - Kaitlin R. Carroll
AU  - Jonathan D. Katz
AU  - Andrew Oberst
AU  - Alexander V. Chervonsky
AU  - Chandrashekhar Pasare
TI  - T cells instruct dendritic cells to produce inflammasome independent IL-1β causing systemic inflammation
AID  - 10.1101/475517
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 475517
4099  - http://biorxiv.org/content/early/2018/11/26/475517.short
4100  - http://biorxiv.org/content/early/2018/11/26/475517.full
AB  - While IL-1β is critical for anti-microbial host defense, it is also a key mediator of autoimmune inflammation. Inflammasome activation following pathogenic insults is known to result in IL-1β production. However, the molecular events that produce IL-1β during T cell driven autoimmune diseases remain unclear. Here, we have discovered an inflammasome-independent pathway of IL-1β production that is triggered upon cognate interactions between dendritic cells and effector CD4 T cells. Analogous to inflammasome activation, this “T cell-instructed IL-1β also relies on two independent signaling events. TNFα produced by activated CD4 T cells engages TNFR signaling on DCs leading to pro-IL-1β synthesis. Subsequently, FasL, also expressed by effector CD4 T cells, engages Fas on DCs leading to caspase-8 dependent pro-IL-1β cleavage. Remarkably, this two-step mechanism is completely independent of pattern recognition receptor activation. IL-1β produced upon cognate DC-effector CD4 T cell interaction causes wide spread leukocyte infiltration, a hallmark of systemic inflammation as well as autoimmune pathology. This study has uncovered a novel feature of DC-T cell cross-talk that allows for active IL-1β secretion independent of innate sensing pathways and provides a mechanistic explanation for IL-1β production and its downstream consequences in CD4 T cell driven autoimmune pathology.