美国辛辛那提儿童医院医疗中心Chandrashekhar Pasare课题组近日取得一项新成果。他们发现T细胞指导髓样细胞产生不依赖于炎性小体的IL-1β并引起自身免疫。该研究于2019年12月17日发表于国际一流学术期刊《自然—免疫学》。

研究人员报道了IL-1β产生的一种不依赖炎症小体的途径，其在CD4⁺效应T细胞和单核吞噬细胞（MP）之间的同源相互作用后触发的。活化的CD4⁺T细胞产生的细胞因子TNF与MP上的受体TNFR结合，导致前IL-1β的合成。CD4⁺T细胞表达的膜结合FasL蛋白激活MP中的死亡受体Fas信号转导，导致caspase-8依赖的前IL-1β切割。T细胞引起的IL-1β导致全身炎症，而TNFR或Fas信号的缺失保护小鼠免受CD4⁺T细胞引起的自身免疫。TNFR–Fas–caspase-8依赖性途径为IL-1β产生及其在CD4⁺T细胞驱动的自身免疫病理后果提供了机制解释。

据介绍，细胞因子白介素（IL）-1β是抗微生物免疫以及自身免疫炎症的关键介导因子。IL-1β的产生需要先天免疫受体信号转导以及炎性小体切割后成熟。目前尚不清楚这种机制是否适用于在T细胞引起的自身免疫性疾病中所观察到的IL-1β产生。

附：英文原文

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

Author: Aakanksha Jain, Ricardo A. Irizarry-Caro, Margaret M. McDaniel, Amanpreet Singh Chawla, Kaitlin R. Carroll, Garrett R. Overcast, Naomi H. Philip, Andrew Oberst, Alexander V. Chervonsky, Jonathan D. Katz, Chandrashekhar Pasare

Issue&Volume: 2019-12-17

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

DOI: 10.1038/s41590-019-0559-y

Source: https://www.nature.com/articles/s41590-019-0559-y