Differential recruitment and activation of mucosal and systemic ILC for improved vaccine design

Abstract

Abstract Innate lymphoid cells (ILC) have emerging roles in immune modulation, tissue homeostasis, and inflammation. ILC may function as innate counterparts of T cells, influencing early host responses against infection or vaccination, potentially modulating development of adaptive immune responses. Little is known, however, of their recruitment and activation following immunization. Here, we investigated the activity of ILC populations after immunization with poxvirus-based vaccine vectors. Our data suggest that fowlpox virus (FPV) and modified vaccinia Ankara strain (MVA) vectors can differentially polarize ILC responses at mucosae. Intranasal (IN) delivery of FPV vectors increased numbers of pulmonary ILC1 and ILC3 subsets expressing IL-17a and IL-22 through 72 hours post-immunization. In contrast, MVA vectors given IN enhanced pulmonary ILC2 numbers and their expression of IL-13. Our previous work indicated that mucosal immunization with these vectors induced high avidity T cell responses associated with transient inhibition of IL-4/13 expression by local ILC2. Since IL-25 has been shown to down regulate IL-12 and promote ILC2/IL-13 expression, we delivered FPV encoding an IL-25 binding protein (IL-25BP) in order to sequester host IL-25 at the site of immunization. While mucosal delivery of FPV-IL-25BP appeared to induce ILC2/IL-13 expression in the lungs, IM delivery reduced ILC2/IL-13 expression, increased IL-17a expression by local ILC1 and ILC3, and enhanced Th1-type adaptive immune responses against co-expressed vaccine antigens. Together, our findings suggest that manipulation of ILC responses by vaccine vectors, co-expressed immune modulators, and delivery route may be exploited for improved vaccine design.