Unique IL-13Rα2/STAT3 mediated IL-13 regulation detected in lung conventional dendritic cells, 24 h post viral vector vaccination

• Published in: Scientific reports Vol. 10; no. 1; p. 1017
• Main Authors: Roy, Sreeja, Liu, Ho-Ying, Jaeson, Muhammad Irwan, Deimel, Lachlan Paul, Ranasinghe, Charani
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 23.01.2020; Nature Publishing Group UK
• Subjects: Animals; Dendritic cells; Dendritic Cells - immunology; Expression vectors; Female; Fowlpox; Fowlpox virus - immunology; Gene expression; Homeostasis; Immunization; Interferon-gamma - immunology; Interleukin 13; Interleukin-13 - immunology; Interleukin-13 Receptor alpha1 Subunit - metabolism; Interleukin-13 Receptor alpha2 Subunit - metabolism; Lung - cytology; Lung - immunology; Mice; Mice, Inbred BALB C; Mice, Knockout; mRNA stability; Stat3 protein; STAT3 Transcription Factor - metabolism; Stat6 protein; STAT6 Transcription Factor - metabolism; Transforming Growth Factor beta1 - immunology; Transforming growth factor-b1; Vaccination; Vaccines; Vaccines, Synthetic - immunology; Vaccinia; Vaccinia virus - immunology; Vectors (Biology); Viral Vaccines - immunology; γ-Interferon
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-57815-z

This study demonstrates that 24 h following viral vector-based vaccination IL-13Rα2 functions as a master sensor on conventional dendritic cells (cDCs), abetted by high protein stability coupled with minimal mRNA expression, to rapidly regulate DC mediated IL-13 responses at the lung mucosae, unlike IL-13Rα1. Under low IL-13, IL-13Rα2 performs as a primary signalling receptor, whilst under high IL-13, acts to sequester IL-13 to maintain homeostasis, both in a STAT3-dependent manner. Likewise, we show that viral vector-derived IL-13 levels at the vaccination site can induce differential STAT3/STAT6 paradigms in lung cDC, that can get regulated collaboratively or independently by TGF-β1 and IFN-γ. Specifically, low IL-13 responses associated with recombinant Fowlpox virus (rFPV) is regulated by early IL-13Rα2, correlated with STAT3/TGF-β1 expression. Whilst, high IL-13 responses, associated with recombinant Modified Vaccinia Ankara (rMVA) is regulated in an IL-13Rα1/STAT6 dependent manner associated with IFN-γR expression bias. Different viral vaccine vectors have previously been shown to induce unique adaptive immune outcomes. Taken together current observations suggest that IL-13Rα2-driven STAT3/STAT6 equilibrium at the cDC level may play an important role in governing the efficacy of vector-based vaccines. These new insights have high potential to be exploited to improve recombinant viral vector-based vaccine design, according to the pathogen of interest and/or therapies against IL-13 associated disease conditions.