Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response.
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.
Sundrud
Mark S
MS
Department of Pathology, Harvard Medical School and Immune Disease Institute, Boston, MA 02115, USA.
Koralov
Sergei B
SB
Feuerer
Markus
M
Calado
Dinis Pedro
DP
Kozhaya
Aimee Elhed
AE
Rhule-Smith
Ava
A
Lefebvre
Rachel E
RE
Unutmaz
Derya
D
Mazitschek
Ralph
R
Waldner
Hanspeter
H
Whitman
Malcolm
M
Keller
Tracy
T
Rao
Anjana
A
D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D015551:Autoimmunity / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics; D038041:Lymphopoiesis / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D052999:Quinazolinones / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
D000596:Amino Acids; C081452:Atf4 protein, mouse; D016207:Cytokines; D015852:Eukaryotic Initiation Factor-2; D020381:Interleukin-17; D010880:Piperidines; D052999:Quinazolinones; D051701:Activating Transcription Factor 4; C529271:EIF2AK4 protein, human; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases; C010176:halofuginone