Dendritic cell-derived TGF-β mediates the induction of mucosal regulatory T-cell response toHelicobacterinfection essential for maintenance of immune tolerance in mice

Background Helicobacter pyloriinfection leads to regulatory T-cell (Treg) induction in infected mice, which contributes toH. pyloriimmune escape. However, the mechanisms responsible forH. pyloriinduction of Treg and immune tolerance remain unclear. We hypothesized DC-produced TGF-beta may be responsible for Treg induction and immune tolerance. Materials and Methods To test this hypothesis, we generated TGF-beta( increment DC)mice (CD11c(+)DC-specific TGF-beta deletion) and assessed the impact of DC-specific TGF-beta deletion on DC function duringHelicobacterinfection in vitro and in vivo. To examine the T cell-independent DC function, we crossed TGF-beta( increment DC)mice onto Rag1KO background to generate TGF-beta( increment DC)xRag1KO mice. Results When stimulated withH. pylori, TGF-beta(BMDC)-B- increment DC/splenocyte cocultures showed increased levels of proinflammatory cytokines and decreased levels of anti-inflammatory cytokines compared to control, indicating a proinflammatory DC phenotype. Following 6 months ofH. felisinfection, TGF-beta( increment DC)mice developed more severe gastritis and a trend toward more metaplasia compared to TGF-beta(fl/fl)with increased levels of inflammatory Th1 cytokine mRNA and lower gastricH. feliscolonization compared to infected TGF-beta(fl/fl)mice. In a T cell-deficient background using TGF-beta( increment DC)xRag1KO mice,H. feliscolonization was significantly lower when DC-derived TGF-beta was absent, revealing a direct, innate function of DC in controllingH. felisinfection independent of Treg induction. Conclusions Our findings indicate that DC-derived TGF-beta mediatesHelicobacter-induced Treg response and attenuates the inflammatory Th1 response. We also demonstrated a previously unrecognized innate role of DC controllingHelicobactercolonization via a Treg-independent mechanism. DC TGF-beta signaling may represent an important target in the management ofH. pylori.