Suppression of host adaptive immune responses by Neisseria gonorrhoeae: role of interleukin 10 and type 1 regulatory T cells

Abstract

Infection with Neisseria gonorrhoeae triggers an intense inflammatory response characterized by an influx of neutrophils in the genital tract, yet natural gonococcal infection does not induce a state of protective immunity. Our previous studies in a mouse model of N. gonorrhoeae infection demonstrated that TGF-β is involved in the suppression of adaptive immunity by this organism, but complete inhibition of TGF-β activity only partially reverses N. gonorrhoeae-mediated suppression of Th1 and Th2 responses. In this study, we show that N. gonorrhoeae strongly induced the production of IL-10 and type 1 regulatory T (Tr1) cells. Blockade of IL-10 and Tr1 cell activity enhanced both Th1/Th2-dependent adaptive immune responses and Th17-governed innate responses to N. gonorrhoeae. Treatment of mice with anti-IL-10 antibody during gonococcal challenge led to faster clearance of infection and induced protection against secondary infection, with the generation of circulating and vaginal anti-gonococcal antibodies. Our results suggest that inhibition of IL-10 and Tr1 cells affords a new approach to the treatment of gonorrhea and facilitates the development of specific protective immunity.

Immunity to Sexually Transmitted Infections

“…Indeed a population of CD3 + /TCRαβ + cells having regulatory activity, though lacking both CD8 and CD4, was found in the mouse genital tract (Johansson and Lycke, 2003). Foxp3 + Treg cells and IL-10-dependent type 1 regulatory T cells have been described in the mouse model of vaginal gonococcal infection (Imarai et al, 2008;Liu et al, 2014). The role of Th17 and regulatory T cells in genital tract infections requires further investigation.…”

Animal Models of Immunity to Female Genital Tract Infections and Vaccine Development

“…Estradiol-treated mice develop a transient and insignificant humoral response to N. gonorrhoeae infection, and there is no evidence of a humoral memory response or protective response against reinfection with the same strain compared with naïve age-matched, estradiol-treated control mice (Song et al, 2008). Recent studies have shown that N. gonorrhoeae suppresses the development of Th1-and Th2-driven adaptive immune responses by mechanisms dependent on TGF-β and IL-10 and by inducing type 1 regulatory T cells (Imarai et al, 2008;Liu et al, 2012Liu et al, , 2014 (Figure 2). Treatment of mice with blocking antibodies against TGFβ reverses gonococcal-induced immunosuppression, enabling Th1-and Th2-dependent responses with circulating and vaginal anti-Gc antibodies, immunological memory, and protective immunity against re-infection .…”

Could Vaccination Against Neisseria Gonorrhoeae be on the Horizon?

“…The first of these, is the recent findings that N. gonorrhoeae proactively manipulates the host immune response for its own benefit, by selectively eliciting innate host defenses that it can survive while concomitantly suppressing adaptive immune responses that would eliminate it [11]. Several mechanisms have been described that contribute to this ability, including inactivation of T-helper cells [12], modulation of dendritic cells or macrophages [13,14] and upregulation of IL-10, TGF-β and type 1 regulatory T cells [15]. These findings reveal new understandings of immunity to N. gonorrhoeae and suggest that novel approaches to reverse gonococcus-induced immunosuppression might be fruitful; moreover they inform new strategies for vaccine development.…”