title: Proprotein convertase FURIN constrains Th2 differentiation and is critical for host resistance against Toxoplasma gondii.
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.
authors.affiliation: Laboratory of Immunoregulation, BioMediTech, University of Tampere, 33014 Tampere, Finland;
authors.forename: Anna
authors.initials: A
authors.lastname: Oksanen
authors.affiliation: Laboratory of Immunoregulation, BioMediTech, University of Tampere, 33014 Tampere, Finland;
authors.forename: Saara
authors.initials: S
authors.lastname: Aittomäki
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Dragana
authors.initials: D
authors.lastname: Jankovic
authors.affiliation: Laboratory of Immunoregulation, BioMediTech, University of Tampere, 33014 Tampere, Finland;
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Ortutay
authors.affiliation: Laboratory of Immunoregulation, BioMediTech, University of Tampere, 33014 Tampere, Finland;
authors.forename: Kati
authors.initials: K
authors.lastname: Pulkkinen
authors.affiliation: Laboratory of Immunoregulation, BioMediTech, University of Tampere, 33014 Tampere, Finland;
authors.forename: Sanna
authors.initials: S
authors.lastname: Hämäläinen
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland;
authors.forename: Anne
authors.initials: A
authors.lastname: Rokka
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland; Van't Hoff Institute for Molecular Sciences, University of Amsterdam, 1090 GD Amsterdam, the Netherlands;
authors.forename: Garry L
authors.initials: GL
authors.lastname: Corthals
authors.affiliation: Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892; Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602;
authors.forename: Wendy T
authors.initials: WT
authors.lastname: Watford
authors.affiliation: Fimlab Laboratories, Pirkanmaa Hospital District, 33101 Tampere, Finland; School of Medicine, University of Tampere, 33014 Tampere, Finland; and.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Junttila
authors.affiliation: Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Shea
authors.affiliation: Laboratory of Immunoregulation, BioMediTech, University of Tampere, 33014 Tampere, Finland; Fimlab Laboratories, Pirkanmaa Hospital District, 33101 Tampere, Finland; Department of Dermatology, Pirkanmaa Hospital District, 33101 Tampere, Finland marko.pesu@uta.fi.
authors.forename: Marko
authors.initials: M
authors.lastname: Pesu
mesh_terms: D000199:Actins / Q000378:metabolism; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D045683:Furin / Q000235:genetics / Q000378:metabolism*; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D007109:Immunity; D019169:Jurkat Cells; D011485:Protein Binding; D050797:STAT4 Transcription Factor / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D014122:Toxoplasma / Q000276:immunology*; D014123:Toxoplasmosis / Q000276:immunology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; D016207:Cytokines; C402110:DOCK2 protein, human; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; D045683:Furin; D020830:rac1 GTP-Binding Protein