Toll-like receptor-dependent activation of antigen-presenting cells affects adaptive immunity to Helicobacter pylori

作者：Rad Roland^*; Brenner Lena; Krug Anne; Voland Petra; Mages Joerg; Lang Roland; Schwendy Susanne; Reindl Wolfgang; Dossumbekova Anar; Ballhorn Wibke; Wagner Hermann; Schmid Roland M; Bauer Stefan; Prinz Christian

来源：Gastroenterology, 2007, 133(1): 150-163.

DOI：10.1053/j.gastro.2007.04.071

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 I 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.

• 出版日期2007-7
• 单位河北医科大学