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J Allergy Clin Immunol. 2017 May;139(5):1650-1666. doi: 10.1016/j.jaci.2016.08.044. Epub 2016 Oct 14.

Protein kinase Cθ controls type 2 innate lymphoid cell and TH2 responses to house dust mite allergen.

Author information

1
Laboratory of experimental and molecular immunology and neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, Orleans, France; Artimmune SAS, Orleans, France.
2
Laboratory of experimental and molecular immunology and neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, Orleans, France.
3
Research Department, Stallergenes Greer, Antony, France.
4
Artimmune SAS, Orleans, France.
5
INSERM, U866, Dijon, France.
6
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.
7
Artimmune SAS, Orleans, France. Electronic address: dieudo.togbe@artimmune.com.

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.

OBJECTIVES:

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.

KEYWORDS:

House dust mite; allergic asthma; eosinophils; innate lymphoid cells; interferon regulatory factor 4; nuclear factor of activated T cells; protein kinase Cθ

PMID:
27746240
DOI:
10.1016/j.jaci.2016.08.044
[Indexed for MEDLINE]

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