Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
J Exp Med. 2019 Feb 4;216(2):369-383. doi: 10.1084/jem.20180722. Epub 2019 Jan 22.
Acquisition of self-reactive effector CD4 T cells is a major component of the autoimmune response that can occur during myocarditis, an inflammatory form of cardiomyopathy. Although the processes by which self-reactive T cells gain effector function have received considerable attention, how these T cells contribute to effector organ inflammation and damage is less clear. Here, we identified an IL-3-dependent amplification loop that exacerbates autoimmune inflammation. In experimental myocarditis, we show that effector organ-accumulating autoreactive IL-3 CD4 T cells stimulate IL-3R tissue macrophages to produce monocyte-attracting chemokines. The newly recruited monocytes differentiate into antigen-presenting cells that stimulate local IL-3 CD4 T cell proliferation, thereby amplifying organ inflammation. Consequently, mice resist developing robust autoimmune inflammation and myocardial dysfunction, whereas therapeutic IL-3 targeting ameliorates disease. This study defines a mechanism that orchestrates inflammation in myocarditis, describes a previously unknown function for IL-3, and identifies IL-3 as a potential therapeutic target in patients with myocarditis.
自身反应性效应 CD4 T 细胞的获得是心肌炎（一种炎症性心肌病）等自身免疫反应的主要组成部分。虽然自身反应性 T 细胞获得效应功能的过程受到了相当多的关注，但这些 T 细胞如何导致效应器官炎症和损伤尚不清楚。在这里，我们确定了一个依赖于 IL-3 的扩增环，该环加剧了自身免疫炎症。在实验性心肌炎中，我们表明，效应器官蓄积的自身反应性 IL-3 CD4 T 细胞刺激 IL-3R 组织巨噬细胞产生单核细胞趋化因子。新募集的单核细胞分化为抗原呈递细胞，刺激局部 IL-3 CD4 T 细胞增殖，从而放大器官炎症。因此，IL-3 敲除小鼠抵抗形成强烈的自身免疫炎症和心肌功能障碍，而治疗性 IL-3 靶向治疗可改善疾病。本研究定义了心肌炎中炎症的协调机制，描述了 IL-3 的一个以前未知的功能，并将 IL-3 确定为心肌炎患者的潜在治疗靶点。
