Self-reactive CD4+ IL-3+ T cells amplify autoimmune inflammation in myocarditis by inciting monocyte chemotaxis
Self-reactive CD4+ IL-3+ T cells amplify autoimmune inflammation in myocarditis by inciting monocyte chemotaxis
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DOI：
10.1084/jem.20180722
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发表时间：
2019-02-01
影响因子：
15.3
通讯作者：
Swirski, Filip K.
中科院分区：
文献类型：
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作者：
Anzai, Atsushi;Mindur, John E.;Swirski, Filip K.
获得自身反应性效应CD 4（+）T细胞是心肌炎（心肌病的一种炎症形式）期间可能发生的自身免疫反应的主要组成部分。尽管自身反应性T细胞获得效应器功能的过程受到了相当大的关注，但这些T细胞如何促进效应器器官炎症和损伤尚不清楚。在这里，我们确定了一个IL-3依赖性放大环，加剧自身免疫性炎症。在实验性心肌炎中，我们发现效应器官积累的自身反应性IL-3（+）CD 4（+）T细胞刺激IL-3R（+）组织巨噬细胞产生单核细胞吸引趋化因子。新募集的单核细胞分化为抗原呈递细胞，刺激局部IL-3（+）CD 4（+）T细胞增殖，从而放大器官炎症。因此，IL-3（-/-）小鼠抵抗发展强烈的自身免疫性炎症和心肌功能障碍，而治疗性IL-3靶向改善疾病。这项研究定义了心肌炎炎症的机制，描述了IL-3以前未知的功能，并确定IL-3作为心肌炎患者的潜在治疗靶点。
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, Il3(-/-) 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.