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 T_H2 cell activation and proliferation. Type 2 innate lymphoid cells (ILC2s) resemble T_H2 cells and produce the T_H2 cytokines IL-5 and IL-13 but lack antigen-specific receptors. The mechanism by which PKC-θ drives innate immune cells to instruct T_H2 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 T_H2 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, T_H2-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, T_H2 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 T_H2 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 T_H2 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.