Cell-autonomous Hedgehog signaling controls Th17 polarization and pathogenicity

Joachim Hanna, Flavio Beke, Louise M. O’Brien, Chrysa Kapeni, Hung-Chang Chen, Valentina Carbonaro, Alexander B. Kim, Kamal Kishore, Timon E. Adolph, Mikkel-Ole Skjoedt, Karsten Skjoedt, Marc Roche and Maike Roche ()
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Joachim Hanna: Cancer Research UK Cambridge Institute, University of Cambridge
Flavio Beke: Cancer Research UK Cambridge Institute, University of Cambridge
Louise M. O’Brien: Cancer Research UK Cambridge Institute, University of Cambridge
Chrysa Kapeni: Cancer Research UK Cambridge Institute, University of Cambridge
Hung-Chang Chen: Cancer Research UK Cambridge Institute, University of Cambridge
Valentina Carbonaro: Cancer Research UK Cambridge Institute, University of Cambridge
Alexander B. Kim: Cancer Research UK Cambridge Institute, University of Cambridge
Kamal Kishore: Cancer Research UK Cambridge Institute, University of Cambridge
Timon E. Adolph: Medical University Innsbruck
Mikkel-Ole Skjoedt: Rigshospitalet - University Hospital Copenhagen
Karsten Skjoedt: University of Southern Denmark
Marc Roche: Department of Biochemistry, University of Cambridge
Maike Roche: Cancer Research UK Cambridge Institute, University of Cambridge

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Th17 cells are key drivers of autoimmune disease. However, the signaling pathways regulating Th17 polarization are poorly understood. Hedgehog signaling regulates cell fate decisions during embryogenesis and adult tissue patterning. Here we find that cell-autonomous Hedgehog signaling, independent of exogenous ligands, selectively drives the polarization of Th17 cells but not other T helper cell subsets. We show that endogenous Hedgehog ligand, Ihh, signals to activate both canonical and non-canonical Hedgehog pathways through Gli3 and AMPK. We demonstrate that Hedgehog pathway inhibition with either the clinically-approved small molecule inhibitor vismodegib or genetic ablation of Ihh in CD4+ T cells greatly diminishes disease severity in two mouse models of intestinal inflammation. We confirm that Hedgehog pathway expression is upregulated in tissue from human ulcerative colitis patients and correlates with Th17 marker expression. This work implicates Hedgehog signaling in Th17 polarization and intestinal immunopathology and indicates the potential therapeutic use of Hedgehog inhibitors in the treatment of inflammatory bowel disease.

Date: 2022
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DOI: 10.1038/s41467-022-31722-5

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