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Document type:
Journal Article; Research Support, Non-U.S. Gov't
Rad, R; Brenner, L; Krug, A; Voland, P; Mages, J; Lang, R; Schwendy, S; Reindl, W; Dossumbekova, A; Ballhorn, W; Wagner, H; Schmid, RM; Bauer, S; Prinz, C
Toll-like receptor-dependent activation of antigen-presenting cells affects adaptive immunity to Helicobacter pylori.
BACKGROUND & AIMS: Recognition of infection leads to induction of adaptive immunity through activation of antigen-presenting cells (APCs). Among APCs, dendritic cells (DCs) have the unique capacity to deliver antigens from the periphery to T cells in secondary lymphoid organs. METHODS: We analyzed molecular mechanisms of the Helicobacter pylori-induced APC activation in vitro and investigated the influence of Myd88 signaling on the phenotype of adaptive immunity to H pylori in a murine infection model. RESULTS: The adaptor protein Myd88 mediates Toll-like receptor (TLR), interleukin (IL)-1, and IL-18 signaling. DCs from wild-type, IL-1R(-/-), and IL-18(-/-) mice responded to H pylori with secretion of proinflammatory cytokines and up-regulation of major histocompatibility complex II and costimulatory molecules. In Myd88(-/-) DCs these processes were impaired profoundly, showing that TLR-dependent H pylori-sensing affects DC activation. Analysis of the H pylori-specific DC transcriptome revealed that large parts of the bacteria-induced transcriptional changes depended on Myd88 signaling, comprising numerous genes involved in crucial steps of immune regulation, such as DC maturation/differentiation, antigen uptake/presentation, and effector cell recruitment/activation. The impaired ability of Myd88(-/-) DCs, B cells, and macrophages to mount a proinflammatory response to H pylori in vitro was reflected in vivo by reduced gastric inflammation and increased bacterial colonization in Myd88-deficient mice. Furthermore, Helicobacter-specific IgG2c/IgG1 ratios were reduced in Myd88(-/-) animals, suggesting the involvement of the Myd88-dependent pathway in the instruction of adaptive immunity toward a T helper cell type 1 phenotype. CONCLUSIONS: A principal pathway by which DCs sense H pylori and become activated is the TLR-dependent signaling cascade. In vivo, Myd88 signaling affects adaptive immunity to the bacterium.
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II. Medizinische Klinik und Poliklinik (Gastroenterologie); Institut für Medizinische Mikrobiologie, Immunologie und Hygiene