TY - JOUR
T1 - Self-reactive CD4+ IL-3+ T cells amplify autoimmune inflammation in myocarditis by inciting monocyte chemotaxis
AU - Anzai, Atsushi
AU - Mindur, John E.
AU - Halle, Lennard
AU - Sano, Soichi
AU - Choi, Jennifer L.
AU - He, Shun
AU - McAlpine, Cameron S.
AU - Chan, Christopher T.
AU - Kahles, Florian
AU - Valet, Colin
AU - Fenn, Ashley M.
AU - Nairz, Manfred
AU - Rattik, Sara
AU - Iwamoto, Yoshiko
AU - Fairweather, De Lisa
AU - Walsh, Kenneth
AU - Libby, Peter
AU - Nahrendorf, Matthias
AU - Swirski, Filip K.
N1 - Publisher Copyright:
© 2019 Anzai et al.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20180722
DO - 10.1084/jem.20180722
M3 - Article
C2 - 30670465
AN - SCOPUS:85061143073
SN - 0022-1007
VL - 216
SP - 369
EP - 383
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 2
ER -