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

Abstract

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...

Mucosal IL-4R antagonist HIV vaccination with SOSIP-gp140 booster can induce high-quality cytotoxic CD4+/CD8+ T cells and humoral responses in macaques

“…In this study AddaVax was used with the SOSIP gp140 booster. However, taken together our recent findings 21 , 24 , 25 (S.Fig. 12 ), we find that selecting an adjuvant that can induce much lower ILC2-derived IL-13 may prove useful in inducing more robust/improved Env-specific immune outcomes with our SOSIP gp140 booster strategy in a clinical setting.…”

“…When unravelling the immune mechanisms linked to our vaccines, we have shown that IL-4R antagonist adjuvanted vaccine induce significantly reduced ILC2-derived IL-13 at the vaccination site 24 h post-delivery compared to the control 17 , responsible for the observed immune outcomes 24,26 . Recently, using range of viral vector-based vaccines we have also demonstrated that ILC-derived IL-13 is the master regulator of different ILC subsets, as well as DC activity at the early stage of vaccination, shaping the downstream adaptive immune outcomes [17][18][19][20][21]23 . Specifically, although IL-13 is known to be detrimental for high avidity T cell induction 13,15,23 , low IL-13 at the vaccination site has shown to be crucial for effective antibody differentiation/ formation 24,25 .…”

“…When trying to unravel the mechanisms behind mucosal verses systemic delivery upon vaccine outcomes, we have recently found that innate lymphoid cells type 2 (ILC2)-derived IL-13 at the vaccination site plays an important role in shaping the downstream adaptive immune outcomes in mice 17 – 19 . Specifically, reduced IL-13 at the vaccination site associated with mucosal delivery leads to recruitment of conventional dendritic cells 18 , 20 , 21 , resulting in high avidity/poly-functional CD8 + T cells, with low or no IL-13 expression 13 , 22 , 23 . Moreover, we have also shown that although IL-13 is detrimental for high avidity T cell induction, the presence of low level of IL-13 is necessary for effective B cell immunity 24 , 25 .…”

GM-CSF and IL-33 Orchestrate Polynucleation and Polyploidy of Resident Murine Alveolar Macrophages in a Murine Model of Allergic Asthma

“…This could be the result of an alternative use of IL-13Ra2/STAT3 signaling rather IL-13Ra1/STAT6 in tAMs. Indeed, IL-13Ra2 has been shown to contribute to allergic asthma [ 40 ] and plays a unique role in the function of conventional pulmonary dendritic cells [ 41 ]. In contrast, although IL-33 influences polarization of alveolar macrophages [ 42 ], there is limited evidence for a role of IL-33 in the formation of giant cells, although it may be a decisive pro-inflammatory cytokine contributing to the pathology of Giant Cell Arteritis [ 43 ].…”

IL-13Rα2 Regulates the IL-13/IFN-γ Balance during Innate Lymphoid Cell and Dendritic Cell Responses to Pox Viral Vector-Based Vaccination

“…IL-13 can also bind to IL-13Rα1 of the type II IL-4 receptor complex, with low affinity (nM concentrations) and initiate signaling via the JAK/STAT6 pathway [ 8 ]. Furthermore, under low IL-13 conditions (pM concentrations), IL-13 is also thought to signal via the not well-characterized IL-13Rα2 pathway [ 13 ], involving STAT3 and activation of TGF-β1 [ 14 ]. Several studies have now shown that IL-13Rα2 can bind to IL-4Rα cytoplasmic tail and inhibit IL-4/IL-13 signaling via the IL-13Rα1/IL-4Rα type II complex and JAK/STAT6 [ 15 , 16 , 17 , 18 ].…”