Halofuginone Inhibits T H 17 Cell Differentiation by Activating the Amino Acid Starvation Response

Author:

Sundrud Mark S.1,Koralov Sergei B.1,Feuerer Markus2,Calado Dinis Pedro1,Kozhaya Aimee ElHed3,Rhule-Smith Ava4,Lefebvre Rachel E.1,Unutmaz Derya3,Mazitschek Ralph565,Waldner Hanspeter4,Whitman Malcolm7,Keller Tracy7,Rao Anjana1

Affiliation:

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. Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.

Abstract

Starving T Cells The T H 17 lineage of CD4 + helper T cells, characterized by the ability to secrete IL-17, is an important mediator of inflammation and autoimmunity. Dampening the responses of these cells or inhibiting their differentiation is of great therapeutic interest. Sundrud et al. (p. 1334 ; see the Perspective by Blander and Amsen ) now show that the small molecule halofuginone inhibits the differentiation of T H 17 cells but not other CD4 + T cell helper lineages both in vitro and in a mouse model of multiple sclerosis. This selective inhibition was mediated by activation of the amino acid starvation response. Amino acid depletion mimicked the effects of halofuginone, whereas excess amino acids rescued T H 17 differentiation. The results highlight the importance of amino acid metabolism in regulating inflammation.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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