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Anna Oksanen, Saara Aittomäki, Dragana Jankovic, Zsuzsanna Ortutay, Kati Pulkkinen, Sanna Hämäläinen, Anne Rokka, Garry L Corthals, Wendy T Watford, Ilkka Junttila, John J O’Shea, Marko Pesu, Proprotein Convertase FURIN Constrains Th2 Differentiation and Is Critical for Host Resistance against Toxoplasma gondii, The Journal of Immunology, Volume 193, Issue 11, December 2014, Pages 5470–5479, https://doi.org/10.4049/jimmunol.1401629
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Abstract
The proprotein convertase subtilisin/kexin enzymes proteolytically convert immature proproteins into bioactive molecules, and thereby they serve as key regulators of cellular homeostasis. The archetype proprotein convertase subtilisin/kexin, FURIN, is a direct target gene of the IL-12/STAT4 pathway and it is upregulated in Th1 cells. We have previously demonstrated that FURIN expression in T cells critically regulates the maintenance of peripheral immune tolerance and the functional maturation of pro–TGF-β1 in vivo, but FURIN’s role in cell-mediated immunity and Th polarization has remained elusive. In this article, we show that T cell–expressed FURIN is essential for host resistance against a prototypic Th1 pathogen, Toxoplasma gondii, and for the generation of pathogen-specific Th1 lymphocytes, including Th1–IL-10 cells. FURIN-deficient Th cells instead show elevated expression of IL-4R subunit α on cell surface, sensitized IL-4/STAT6 signaling, and a propensity to polarize toward the Th2 phenotype. By exploring FURIN-interacting proteins in Jurkat T cells with Strep-Tag purification and mass spectrometry, we further identify an association with a cytoskeleton modifying Ras-related C3 botulinum toxin substrate/dedicator of cytokinesis 2 protein complex and unravel that FURIN promotes F-actin polymerization, which has previously been shown to downregulate IL-4R subunit α cell surface expression and promote Th1 responses. In conclusion, our results demonstrate that in addition to peripheral immune tolerance, T cell–expressed FURIN is also a central regulator of cell-mediated immunity and Th1/2 cell balance.
