Mycobacterium bovis Bacillus Calmette-Guerin Killed by Extended Freeze-Drying Targets Plasmacytoid Dendritic Cells To Regulate Lung Inflammation

• Published in: The Journal of immunology (1950) Vol. 184; no. 2; pp. 1062 - 1070
• Main Authors: Lagranderie, Micheline, Abolhassani, Mohammad, Vanoirbeek, Jeroen A. J, Lima, Carla, Balazuc, Anne-Marie, Vargaftig, B. Boris, Marchal, Gilles
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.01.2010
• Subjects: Animals; BCG Vaccine - administration & dosage; BCG Vaccine - pharmacology; Dendritic Cells - drug effects; Freeze Drying; Lung - immunology; Male; Mice; Mice, Inbred Strains; Mycobacterium bovis; Ovalbumin; Pneumonia - prevention & control; Pneumonia - therapy; PPAR gamma - agonists; Spleen - immunology; T-Lymphocytes, Regulatory; Transcription Factors; Treatment Outcome
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0901822

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.