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

作者：He, Ying; Wang, Yihui; He, Rongze; Abdelsalam, Ahmed Mohamed; Zhong, Guangming^*

来源：Infection and Immunity, 2023, 91(11): e0037123.

DOI：10.1128/iai.00371-23

• oral Chlamydia vaccine
• intrOv
• IFN gamma(+)ILC3s
• IL-23 receptor signaling

An IFN gamma-susceptible mutant of Chlamydia muridarum is attenuated in pathogenicity in the genital tract and was recently licensed as an intracellular Oral vaccine vector 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 IFN gamma 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 IFN gamma that in return inhibited intrOv. The intrOv-IFN gamma interactions were dependent on ROR gamma t, a signature transcriptional factor of ILC3s. Consistently, the transfer of oral intrOv-induced ILC3s from ROR gamma t-GFP reporter mice to IFN gamma-deficient mice rescued the inhibition of intrOv. Thus, IFN gamma 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 IFN gamma-producing LC3s (IFN gamma(+)ILC3s). Interestingly, IL-23 receptor knockout (IL-23R(-/-)) mice no longer inhibited intrOv, which was accompanied by reduced colonic IFN gamma. 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 IFN gamma(+)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.

• 单位
  南方医科大学