Mycobacterium bovis bacillus Calmette-Guérin killed by extended freeze-drying targets plasmacytoid dendritic cells to regulate lung inflammation.
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.
Lagranderie
Micheline
M
Laboratoire d'Immunothérapie, Institut Pasteur, Paris, France.
Abolhassani
Mohammad
M
Vanoirbeek
Jeroen A J
JA
Lima
Carla
C
Balazuc
Anne-Marie
AM
Vargaftig
B Boris
BB
Marchal
Gilles
G
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
D001500:BCG Vaccine; D047495:PPAR gamma; D014157:Transcription Factors; D010047:Ovalbumin