IL-23 receptor signaling licenses group 3-like innate lymphoid cells to restrict a live-attenuated oral Chlamydia vaccine in the gut

Abstract

AbstractAn IFNγ-susceptible mutant ofChlamydia muridarumis attenuated in pathogenicity in the genital tract and recently licensed as anintracellularOral vaccinevector or intrOv. Oral delivery of intrOv induces transmucosal protection in the genital tract but intrOv itself is cleared from the gut (without shedding any infectious particles externally) by IFNγ from group 3-like innate lymphoid cells (ILC3s). We further characterized the intrOv interactions with ILC3s in the current study since the interactions may impact both the safety and efficacy of intrOv as an oral Chlamydia vaccine. Intracolonic inoculation with intrOv induced IFNγ that in return inhibited intrOv. The intrOv-IFNγ interactions were dependent on RORγt, a signature transcriptional factor of ILC3s. Consistently, transfer of oral intrOv-induced ILC3s from RORγt-GFP reporter mice to IFNγ-deficient mice rescued the inhibition of intrOv. Thus, IFNγ produced by intrOv-induced ILC3s is likely responsible for inhibiting intrOv, which is further supported by the observation that oral intrOv did induce significant levels of IFNγ-producing LC3s (IFNγ+ILC3s). Interestingly, IL-23 receptor knockout (IL-23R-/-) mice no longer inhibited intrOv, which was accompanied with reduced colonic IFNγ. Transfer of oral intrOv-induced ILC3s rescued the IL-23R-/-mice to inhibit intrOv, validating the dependence of ILC3s on IL-23R signaling for inhibiting intrOv. Clearly, intrOv induces intestinal IFNγ+ILC3s for its own inhibition in the gut, which is facilitated by IL-23R signaling. These findings have provided a mechanism for ensuring the safety of intrOv as an oral Chlamydia vaccine and a platform for investigating how oral intrOv induces transmucosal protection in the genital tract.SignificanceDespite the extensive efforts, no subunit vaccine is available for protecting humans againstC. trachomatisinfection and pathogenicity. Recent studies have led to a licensed live-attenuated oral vaccine (intrOv) that is both effective in inducing transmucosal protection in the genital tract and safe due to its susceptibility to IFNγ delivered by ILC3s. Characterization of the intrOv interactions with IFNγ-producing ILC3s in the current study has revealed a critical role of IL-23 receptor signaling in facilitating ILC3s to clear intrOv from the gut, which has provided a mechanism for ensuring the safety of intrOv and laid a foundation for further revealing the mechanisms by which oral intrOv induces transmucosal immunity in the genital tract since ILC3s can also function as antigen presenting cells.