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bioRxiv · 10.1101/475517

T cells instruct dendritic cells to produce inflammasome independent IL-1β causing systemic inflammation

Jain, A.·Irizarry-Caro, R. A.·Chawla, A. S.·Philip, N. H.·Carroll, K. R.·Katz, J.·Oberst, A.·Chervonsky, A.·Pasare, C.
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Abstract

While IL-1{beta} 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-1{beta} production. However, the molecular events that produce IL-1{beta} during T cell driven autoimmune diseases remain unclear. Here, we have discovered an inflammasome-independent pathway of IL-1{beta} production that is triggered upon cognate interactions between dendritic cells and effector CD4 T cells. Analogous to inflammasome activation, this \"T cell-instructed IL-1{beta} also relies on two independent signaling events. TNF produced by activated CD4 T cells engages TNFR signaling on DCs leading to pro-IL-1{beta} synthesis. Subsequently, FasL, also expressed by effector CD4 T cells, engages Fas on DCs leading to caspase-8 dependent pro-IL-1{beta} cleavage. Remarkably, this two-step mechanism is completely independent of pattern recognition receptor activation. IL-1{beta} 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-1{beta} secretion independent of innate sensing pathways and provides a mechanistic explanation for IL-1{beta} production and its downstream consequences in CD4 T cell driven autoimmune pathology.

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Jain, A., Irizarry-Caro, R. A., Chawla, A. S., Philip, N. H., Carroll, K. R., Katz, J., Oberst, A., Chervonsky, A., Pasare, C.. 2018-11-26. T cells instruct dendritic cells to produce inflammasome independent IL-1β causing systemic inflammation. https://doi.org/10.1101/475517

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