title: Mycobacterium bovis bacillus Calmette-Guérin killed by extended freeze-drying targets plasmacytoid dendritic cells to regulate lung inflammation.
abstract: We have previously shown that bacillus Calmette-Guérin (BCG) inactivated by extended freeze-drying (EFD) reduces airway hyperresponsiveness, whereas live and heat-killed BCG fail to do so. However, the cells involved in the protective effect and the signaling and transcriptional networks that could reprogram T cell commitment after EFD BCG treatment remained to be elucidated. We investigated whether EFD BCG targets plasmacytoid dendritic cells (pDCs) potentially involved in the polarization of regulatory T cells (Tregs) and the transcriptional factors that regulate allergic inflammation. OVA-sensitized mice were s.c. injected with EFD, live, or heat-killed BCG. We analyzed after the injection of the various BCG preparations: 1) pDCs recruited in the draining lymph nodes (day 4); 2) transcription factors involved in inflammation and T cell commitment in spleen and lungs after OVA challenge (day 28). Airway hyperresponsiveness and transcription factors were determined after in vivo depletion of pDCs or Tregs in EFD BCG-treated and OVA-challenged mice. EFD BCG reduced inflammation via the recruitment of pDCs polarizing the differentiation of naive CD4+ T lymphocytes into Tregs. In vivo, pDC or Treg depletion at the time of EFD BCG treatment abrogated the protection against inflammation. EFD BCG treatment upregulated Forkhead-winged helix transcription factor (Treg signature) and downregulated GATA-3 and RORgammat (Th2 and Th17 signatures) more efficiently than live and heat-killed BCG. Moreover, only EFD BCG enhanced peroxisome proliferator-activated receptor gamma expression and blocked NF-kappaB activation, cyclooxygenase expression, and p38 MAPK phosphorylation. EFD BCG reduced allergic inflammation by recruiting pDCs that promoted Tregs; EFD BCG acted as a peroxisome proliferator-activated receptor gamma agonist and thus could be used in asthma and other inflammatory diseases.
authors.affiliation: Laboratoire d'Immunothérapie, Institut Pasteur, Paris, France.
authors.forename: Micheline
authors.initials: M
authors.lastname: Lagranderie
authors.forename: Mohammad
authors.initials: M
authors.lastname: Abolhassani
authors.forename: Jeroen A J
authors.initials: JA
authors.lastname: Vanoirbeek
authors.forename: Carla
authors.initials: C
authors.lastname: Lima
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Balazuc
authors.forename: B Boris
authors.initials: BB
authors.lastname: Vargaftig
authors.forename: Gilles
authors.initials: G
authors.lastname: Marchal
mesh_terms: D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage / Q000494:pharmacology*; D003713:Dendritic Cells / Q000187:drug effects*; D005612:Freeze Drying; D008168:Lung / Q000276:immunology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009163:Mycobacterium bovis; D010047:Ovalbumin; D047495:PPAR gamma / Q000819:agonists; D011014:Pneumonia / Q000517:prevention & control* / Q000628:therapy; D013154:Spleen / Q000276:immunology; D050378:T-Lymphocytes, Regulatory; D014157:Transcription Factors; D016896:Treatment Outcome
chemical_list: D001500:BCG Vaccine; D047495:PPAR gamma; D014157:Transcription Factors; D010047:Ovalbumin