Endosomal recognition of Lactococcus lactis G121 and its RNA by dendritic cells is key to its allergy-protective effects

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:139

Article

Stein, Karina¹  Brand, Stephanie²  Jenckel, Andre¹  Sigmund, Anna³  Chen, Zhijian James⁴  Kirschning, Carsten J.³  Kauth, Marion²  Heine, Holger¹ 

[1] German Ctr Lung Res DZL, Airway Res Ctr North, Div Innate Immun, Res Ctr Borstel, Giessen, Germany

[2] Protectimmun GmbH, Gelsenkirchen, Germany

[3] Univ Duisburg Essen, Inst Med Microbiol, Essen, Germany

[4] UT Southwestern Med Sch, Howard Hughes Med Inst, Dept Mol Biol, Dallas, TX USA

关键词: Allergy protection;    dendritic cells;    endosomal acidification;    Lactococcus lactis G121;    pattern recognition receptor;    Toll-like receptor 13;    Toll-like receptor 8;    bacterial RNA;   

DOI  :  10.1016/j.jaci.2016.06.018

来源: Elsevier

【 摘 要 】

Background: Bacterial cowshed isolates are allergy protective in mice; however, the underlying mechanisms are largely unknown. We examined the ability of Lactococcus lactis G121 to prevent allergic inflammatory reactions. Objective: We sought to identify the ligands and pattern recognition receptors through which L lactis G121 confers allergy protection. Methods: L lactis G121-induced cytokine release and surface expression of costimulatory molecules by untreated or inhibitortreated (bafilomycin and cytochalasin D) human monocyte-derived dendritic cells (moDCs), bone marrow-derived mouse dendritic cells (BMDCs), and moDC/naive CD4(+) T-cell cocultures were analyzed by using ELISA and flow cytometry. The pathology of ovalbumin-induced acute allergic airway inflammation after adoptive transfer of BMDCs was examined by means of microscopy. Results: L lactis G121-treated murine BMDCs and human moDCs released TH1-polarizing cytokines and induced T(H)1 T cells. Inhibiting phagocytosis and endosomal acidification in BMDCs or moDCs impaired the release of TH1-polarizing cytokines, costimulatory molecule expression, and T-cell activation on L lactis G121 challenge. In vivo allergy protection mediated by L lactis G121 was dependent on endosomal acidification in dendritic cells (DCs). Toll-like receptor (Tlr) 13(-/-) BMDCs showed a weak response to L lactis G121 and were unresponsive to its RNA. The TH1-polarizing activity of L lactis G121-treated human DCs was blocked by TLR8-specific inhibitors, mediated by L lactis G121 RNA, and synergistically enhanced by activation of nucleotide-binding oligomerization domain-containing protein (NOD) 2. Conclusion: Bacterial RNA is the main driver of L lactis G121-mediated protection against experimentally induced allergy and requires both bacterial uptake by DCs and endosomal acidification. In mice L lactis G121 RNA signals through TLR13; however, the most likely intracellular receptor in human subjects is TLR8.

【 授权许可】

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