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Science 324 (5932): 1334-1338

Copyright © 2009 by the American Association for the Advancement of Science

Halofuginone Inhibits TH17 Cell Differentiation by Activating the Amino Acid Starvation Response

Mark S. Sundrud,1 Sergei B. Koralov,1 Markus Feuerer,2 Dinis Pedro Calado,1 Aimee ElHed Kozhaya,3 Ava Rhule-Smith,4 Rachel E. Lefebvre,1 Derya Unutmaz,3 Ralph Mazitschek,5,6,7 Hanspeter Waldner,4 Malcolm Whitman,8,* Tracy Keller,8,* Anjana Rao1,*

Abstract: A central challenge for improving autoimmune therapy is preventing inflammatory pathology without inducing generalized immunosuppression. T helper 17 (TH17) 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 TH17 differentiation by activating a cytoprotective signaling pathway, the amino acid starvation response (AAR). Inhibition of TH17 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 TH17-associated experimental autoimmune encephalomyelitis. These results indicate that the AAR pathway is a potent and selective regulator of inflammatory T cell differentiation in vivo.

1 Department of Pathology, Harvard Medical School and Immune Disease Institute, Boston, MA 02115, USA.
2 Section on Immunology and Immunogenetics, Joslin Diabetes Center, Boston, MA 02215, USA.
3 Department of Microbiology and The Microbial Pathogenesis Program, New York University School of Medicine, New York, NY 10016, USA.
4 Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
5 Chemical Biology Program, Broad Institute, Cambridge, MA 02142, USA.
6 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02142, USA.
7 Chemical Biology Program, Broad Institute, Cambridge, MA 02142, USA.
8 Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.

* To whom correspondence should be addressed. E-mail: whitman{at}hms.harvard.edu (M.W.); tkeller{at}hms.harvard.edu (T.K.); arao{at}idi.harvard.edu (A.R.)

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