1. Self-reactive CD4+ IL-3+ T cells amplify autoimmune inflammation in myocarditis by inciting monocyte chemotaxis
- Author
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Kenneth Walsh, Matthias Nahrendorf, Shun He, Filip K. Swirski, John E. Mindur, Manfred Nairz, Lennard Halle, Sara Rattik, Soichi Sano, Jennifer L. Choi, Christopher T. Chan, De Lisa Fairweather, Florian Kahles, Ashley M. Fenn, Atsushi Anzai, Colin Valet, Yoshiko Iwamoto, Peter Libby, and Cameron S. McAlpine
- Subjects
CD4-Positive T-Lymphocytes ,0301 basic medicine ,Chemokine ,Myocarditis ,Monocyte chemotaxis ,T cell ,Immunology ,Cardiomyopathy ,Inflammation ,medicine.disease_cause ,Article ,Monocytes ,Autoimmune Diseases ,Autoimmunity ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Immunology and Allergy ,Research Articles ,Cell Proliferation ,Mice, Knockout ,Mice, Inbred BALB C ,biology ,business.industry ,Effector ,Chemotaxis ,Macrophages ,medicine.disease ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,biology.protein ,Interleukin-3 ,medicine.symptom ,business ,030215 immunology - Abstract
In autoimmune myocarditis, self-reactive T cells attack cardiac antigens and contribute to heart inflammation. In this study, Anzai et al. show that the T cell–derived cytokine and growth factor IL-3 amplifies inflammation and exacerbates autoimmune myocarditis., 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.
- Published
- 2019