title: Protein kinase Cθ controls type 2 innate lymphoid cell and TH2 responses to house dust mite allergen.
abstract: BACKGROUND
  Protein kinase C (PKC) θ, a serine/threonine kinase, is involved in TH2 cell activation and proliferation. Type 2 innate lymphoid cells (ILC2s) resemble TH2 cells and produce the TH2 cytokines IL-5 and IL-13 but lack antigen-specific receptors. The mechanism by which PKC-θ drives innate immune cells to instruct TH2 responses in patients with allergic lung inflammation remains unknown.
  
  
  OBJECTIVE
  We hypothesized that PKC-θ contributes to ILC2 activation and might be necessary for ILC2s to instruct the TH2 response.
  
  
  METHODS
  PRKCQ gene expression was assessed in innate lymphoid cell subsets purified from human PBMCs and mouse lung ILC2s. ILC2 activation and eosinophil recruitment, TH2-related cytokine and chemokine production, lung histopathology, interferon regulatory factor 4 (IRF4) mRNA expression, and nuclear factor of activated T cells (NFAT1) protein expression were determined. Adoptive transfer of ILC2s from wild-type mice was performed in wild-type and PKC-θ-deficient (PKC-θ-/-) mice.
  
  
  RESULTS
  Here we report that PKC-θ is expressed in both human and mouse ILC2s. Mice lacking PKC-θ had reduced ILC2 numbers, TH2 cell numbers and activation, airway hyperresponsiveness, and expression of the transcription factors IRF4 and NFAT1. Importantly, adoptive transfer of ILC2s restored eosinophil influx and IL-4, IL-5 and IL-13 production in lung tissue, as well as TH2 cell activation. The pharmacologic PKC-θ inhibitor (Compound 20) administered during allergen challenge reduced ILC2 numbers and activation, as well as airway inflammation and IRF4 and NFAT1 expression.
  
  
  CONCLUSIONS
  Therefore our findings identify PKC-θ as a critical factor for ILC2 activation that contributes to TH2 cell differentiation, which is associated with IRF4 and NFAT1 expression in allergic lung inflammation.
authors.affiliation: Laboratory of experimental and molecular immunology and neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, Orleans, France; Artimmune SAS, Orleans, France.
authors.forename: Fahima
authors.initials: F
authors.lastname: Madouri
authors.affiliation: Laboratory of experimental and molecular immunology and neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, Orleans, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Chenuet
authors.affiliation: Research Department, Stallergenes Greer, Antony, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: Beuraud
authors.affiliation: Artimmune SAS, Orleans, France.
authors.forename: Louis
authors.initials: L
authors.lastname: Fauconnier
authors.affiliation: Artimmune SAS, Orleans, France.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Marchiol
authors.affiliation: Artimmune SAS, Orleans, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rouxel
authors.affiliation: Artimmune SAS, Orleans, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Ledru
authors.affiliation: Artimmune SAS, Orleans, France.
authors.forename: Margaux
authors.initials: M
authors.lastname: Gallerand
authors.affiliation: Research Department, Stallergenes Greer, Antony, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Lombardi
authors.affiliation: Research Department, Stallergenes Greer, Antony, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mascarell
authors.affiliation: Laboratory of experimental and molecular immunology and neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, Orleans, France; Artimmune SAS, Orleans, France.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Marquant
authors.affiliation: INSERM, U866, Dijon, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Apetoh
authors.affiliation: Laboratory of experimental and molecular immunology and neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, Orleans, France.
authors.forename: François
authors.initials: F
authors.lastname: Erard
authors.affiliation: Laboratory of experimental and molecular immunology and neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, Orleans, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Le Bert
authors.affiliation: Artimmune SAS, Orleans, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Trovero
authors.affiliation: Laboratory of experimental and molecular immunology and neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, Orleans, France.
authors.forename: Valérie F J
authors.initials: VFJ
authors.lastname: Quesniaux
authors.affiliation: Laboratory of experimental and molecular immunology and neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, Orleans, France; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, South Africa.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.affiliation: Artimmune SAS, Orleans, France. Electronic address: dieudo.togbe@artimmune.com.
authors.forename: Dieudonnée
authors.initials: D
authors.lastname: Togbe
mesh_terms: D000485:Allergens / Q000276:immunology*; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology*; D001249:Asthma / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002454:Cell Differentiation; D016207:Cytokines / Q000276:immunology; D004151:Dipeptides / Q000494:pharmacology; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D050835:Interferon Regulatory Factors / Q000276:immunology; D007527:Isoenzymes / Q000235:genetics / Q000276:immunology*; D007958:Leukocyte Count; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000276:immunology; D011493:Protein Kinase C / Q000235:genetics / Q000276:immunology*; D000074121:Protein Kinase C-theta; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000099218:Interferon Regulatory Factor-4
chemical_list: D000485:Allergens; D039741:Antigens, Dermatophagoides; D016207:Cytokines; D004151:Dipeptides; D050835:Interferon Regulatory Factors; D007527:Isoenzymes; D050778:NFATC Transcription Factors; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D047428:Protein Kinase Inhibitors; D000099218:Interferon Regulatory Factor-4; C028342:compound 20; C489593:Prkcq protein, mouse
keywords: House dust mite; allergic asthma; eosinophils; innate lymphoid cells; interferon regulatory factor 4; nuclear factor of activated T cells; protein kinase Cθ