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. IL-13 and IL-4 share a common signalling receptor system and are known to have overlapping as well as distinct functions 1. These two cytokines have been extensively studied under allergy, asthma, helminth and parasitic infections 2-5. IL-13 is produced by various immune cell types, specifically innate lymphoid cells (ILC2s), CD4 and CD8 T cells 6,7 and can directly impact the function of eosinophils, basophils and dendritic cells (DCs) 8,9. Recent allergy and asthma studies have shown that ILC2-derived IL-13 can stimulate the migration of lung DCs to promote Th2 immunity 10. Interestingly, whilst overproduction of IL-13 is associated with tissue pathology 11 , deficiency of IL-13 has been associated with increased susceptibility to certain skin cancers 12. Moreover, mounting evidence has also suggested the importance of IL-13 regulation in infection and immunity. We have previously demonstrated that the vaccine route, viral vector combination and cytokine milieu (level of IL-13) can significantly alter the adaptive immune outcomes 7,13,14. Pox viral vector-based HIV vaccine strategies that transiently inhibited IL-13 activity at the vaccination site, can induce high avidity/poly-functional T cells both in mice and macaques 15-17 (Li et al. in preparation). Interestingly, 24 h post delivery of these vaccines, whilst ILC2s were found to be the major source of IL-13 at the vaccination site 18 , elevated recruitment of CD11b + CD103 − conventional DCs (cDC) to the lung mucosae were associated with the o...