Dendritic cell-intrinsic TLR/MyD88 signaling promotes the clearance of a live-attenuated oral vaccine

Abstract

A genital tract pathogenicity-attenuated Chlamydia muridarum mutant, named intrOv, is being developed into an oral vaccine against C. trachomatis infection in the genital tract. Although wild-type C. muridarum persists in the mouse large intestine for long periods, intrOv is cleared by the group 3 innate lymphoid cells that produce IFN{gamma} (IFN{gamma}+ILC3s). The current study aims to reveal the mechanism by which intrOv induces IFN{gamma}+ILC3s for its own clearance from the large intestine. IntrOv-induced IL-23 and IL-23 signaling were required for the clearance of intrOv from the large intestine. The intrOv clearance depended on dendritic cells, as depletion of CD11c+ cells reduced both IL-23 and IFN-{gamma}, resulting in the growth of intrOv. Deletion of MyD88 from dendritic cells, but not phagocytes or epithelial cells, rescued the growth of intrOv, indicating a critical role of MyD88 signaling in dendritic cells. Furthermore, TLR2/4 signaling is also essential for inhibiting intrOv, as the deficiency in TLR2/4 fully rescues the growth of intrOv. Both the TLR and MyD88 signaling must be in the same dendritic cells to inhibit intrOv, as the growth of intrOv in the MyD88- or TLR2/4-deficient mice was blocked by only wild-type bone marrow-derived dendritic cells but not dendritic cells deficient in either MyD88 or TLR2/4. Thus, we have demonstrated a dendritic cell-intrinsic TLR/MyD88/IL-23 pathway for recruiting effectors to clear intrOv from the large intestine. The information may help further improve the efficacy and safety of intrOv and guide the design of future mucosal vaccines.