This study demonstrates that modulation of IL-25 and IL-33 cytokines responsible for innate lymphoid cell 2 (ILC2) activation/function can differentially regulate ILC profiles at the vaccination site， in a vaccine route-dependent manner. Specifically， recombinant fowlpox (rFPV) vector-based vaccine co-expressing an adjuvant that transiently sequestered IL-25 (FPV-HIV-IL-25 binding protein)， delivered intramuscularly (i.m.) was able to induce significantly lower IL-25R ILC2-deived IL-13 and ILC1/ILC3-derived IFN-γ expression with significantly elevated IL-17A in muscle. In contrast， intranasal (i.n.) delivery was able to induce all three known ILC2 subsets (ST2/IL-33R， IL-25R， and TSLPR ILC2) to exp... More
This study demonstrates that modulation of IL-25 and IL-33 cytokines responsible for innate lymphoid cell 2 (ILC2) activation/function can differentially regulate ILC profiles at the vaccination site， in a vaccine route-dependent manner. Specifically， recombinant fowlpox (rFPV) vector-based vaccine co-expressing an adjuvant that transiently sequestered IL-25 (FPV-HIV-IL-25 binding protein)， delivered intramuscularly (i.m.) was able to induce significantly lower IL-25R ILC2-deived IL-13 and ILC1/ILC3-derived IFN-γ expression with significantly elevated IL-17A in muscle. In contrast， intranasal (i.n.) delivery was able to induce all three known ILC2 subsets (ST2/IL-33R， IL-25R， and TSLPR ILC2) to express varying amounts of IL-13 in lung， and also the TSLPR ILC2 to express IL-4， unlike the unadjuvanted control， which only showed ST2/IL-33R ILC2 to express IL-13. Interestingly， the sequestration of IL-25 in lung also induced a unique lineage ST2/IL-33R IL-25R TSLPR ILC2 population to express elevated IL-13 and IL-4. Moreover， both i.m. and， i.n. FPV-HIV-IL-25BP vaccination induced significantly elevated ILC1/ILC3-derived IL-17A in lung， indicating that ILC2 could directly impact ILC1/ILC3 activity. To our surprise， transient sequestration of IL-33 at the lung mucosae did not alter the lung ILC2 profiles or activity. These inhibitor studies showed that in the context of i.n. viral vector vaccination， IL-25 plays a predominant role in early ILC development/regulation than IL-33， and likely acts as a master regulator of ILC. Our previous findings have indicated that level of IL-4/IL-13 at the vaccination site impacts the quality/avidity of T cell immunity. Taken together data suggest that IL-25 binding protein could be used as an effective i.m. not an i.n. adjuvant to enhance quality of vaccine-specific T cell immunity. These findings evoke the notion that route-dependent manipulation of ILCs according to the target pathogen could be exploited to design more effective vaccines against chronic pathogens in the future.
