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

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, De Lisa Fairweather, Kenneth Walsh, Peter Libby, Matthias Nahrendorf, Filip K. Swirski

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)369-383
Number of pages15
JournalJournal of Experimental Medicine
Volume216
Issue number2
DOIs
StatePublished - Feb 1 2019

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Anzai, A., Mindur, J. E., Halle, L., Sano, S., Choi, J. L., He, S., McAlpine, C. S., Chan, C. T., Kahles, F., Valet, C., Fenn, A. M., Nairz, M., Rattik, S., Iwamoto, Y., Fairweather, D. L., Walsh, K., Libby, P., Nahrendorf, M., & Swirski, F. K. (2019). Self-reactive CD4+ IL-3+ T cells amplify autoimmune inflammation in myocarditis by inciting monocyte chemotaxis. Journal of Experimental Medicine, 216(2), 369-383. https://doi.org/10.1084/jem.20180722