Journal
SCIENCE
Volume 324, Issue 5932, Pages 1334-1338Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1172638
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Funding
- NIH [T32, P01]
- Juvenile Diabetes Research Foundation
- Irvington Institute fellowship program of the Cancer Research Institute
- Portuguese Foundation for Science and Technology fellowship
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A central challenge for improving autoimmune therapy is preventing inflammatory pathology without inducing generalized immunosuppression. T helper 17 (T(H)17) cells, characterized by their production of interleukin-17, have emerged as important and broad mediators of autoimmunity. Here we show that the small molecule halofuginone (HF) selectively inhibits mouse and human T(H)17 differentiation by activating a cytoprotective signaling pathway, the amino acid starvation response (AAR). Inhibition of T(H)17 differentiation by HF is rescued by the addition of excess amino acids and is mimicked by AAR activation after selective amino acid depletion. HF also induces the AAR in vivo and protects mice from T(H)17-associated experimental autoimmune encephalomyelitis. These results indicate that the AAR pathway is a potent and selective regulator of inflammatory T cell differentiation in vivo.
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