Self-reactive CD4+ IL-3+ T cells amplify autoimmune inflammation in myocarditis by inciting monocyte chemotaxis

• DOI: 10.1084/jem.20180722
• Publication Date: 2019-01-22T19:59:12Z
• Authors: Atsushi Anzai; John E. Mindur; Lennard Halle; Soichi Sano; Jennifer L. Choi; Shun He; Cameron S. McAlpine; Christopher T. Chan; Florian Kahles; Colin Valet; Ashley M. Fenn; Manfred Nairz; Sara Rattik; Yoshiko Iwamoto; DeLisa Fairweather; Kenneth Walsh; Peter Libby; Matthias Nahrendorf; Filip K. Swirski
• Keywords: CD4-Positive T-Lymphocytes; Mice, Knockout; 0301 basic medicine; Mice, Inbred BALB C; 0303 health sciences; Chemotaxis; Macrophages; Monocytes; Autoimmune Diseases; 3. Good health; Mice; Myocarditis; 03 medical and health sciences; Animals; Interleukin-3; Research Articles; Cell Proliferation

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.