title: Spherical lactic acid bacteria activate plasmacytoid dendritic cells immunomodulatory function via TLR9-dependent crosstalk with myeloid dendritic cells.
abstract: Plasmacytoid dendritic cells (pDC) are a specialized sensor of viral and bacterial nucleic acids and a major producer of IFN-α that promotes host defense by priming both innate and acquired immune responses. Although synthetic Toll-like receptor (TLR) ligands, pathogenic bacteria and viruses activate pDC, there is limited investigation of non-pathogenic microbiota that are in wide industrial dietary use, such as lactic acid bacteria (LAB). In this study, we screened for LAB strains, which induce pDC activation and IFN-α production using murine bone marrow (BM)-derived Flt-3L induced dendritic cell culture. Microbial strains with such activity on pDC were absent in a diversity of bacillary strains, but were observed in certain spherical species (Lactococcus, Leuconostoc, Streptococcus and Pediococcus), which was correlated with their capacity for uptake by pDC. Detailed study of Lactococcus lactis subsp. lactis JCM5805 and JCM20101 revealed that the major type I and type III interferons were induced (IFN-α, -β, and λ). IFN-α induction was TLR9 and MyD88-dependent; a slight impairment was also observed in TLR4(-/-) cells. While these responses occurred with purified pDC, IFN-α production was synergistic upon co-culture with myeloid dendritic cells (mDC), an interaction that required direct mDC-pDC contact. L. lactis strains also stimulated expression of immunoregulatory receptors on pDC (ICOS-L and PD-L1), and accordingly augmented pDC induction of CD4(+)CD25(+)FoxP3(+) Treg compared to the Lactobacillus strain. Oral administration of L. lactis JCM5805 induced significant activation of pDC resident in the intestinal draining mesenteric lymph nodes, but not in a remote lymphoid site (spleen). Taken together, certain non-pathogenic spherical LAB in wide dietary use has potent and diverse immunomodulatory effects on pDC potentially relevant to anti-viral immunity and chronic inflammatory disease.
authors.affiliation: Central Laboratories for Frontier Technology, Kirin Holdings Co., Ltd., Kanazawa, Yokohama, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Jounai
authors.forename: Kumiko
authors.initials: K
authors.lastname: Ikado
authors.forename: Tetsu
authors.initials: T
authors.lastname: Sugimura
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Ano
authors.forename: Jonathan
authors.initials: J
authors.lastname: Braun
authors.forename: Daisuke
authors.initials: D
authors.lastname: Fujiwara
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D005260:Female; D007155:Immunologic Factors / Q000276:immunology / Q000378:metabolism; D016898:Interferon-alpha / Q000276:immunology / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D013294:Lactococcus lactis / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D007934:Leuconostoc / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D010376:Pediococcus / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D013291:Streptococcus / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism*
chemical_list: D007155:Immunologic Factors; D016898:Interferon-alpha; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D019344:Lactic Acid