title: Capacity of lung stroma to educate dendritic cells inhibiting mycobacteria-specific T-cell response depends upon genetic susceptibility to tuberculosis.
abstract: The balance between activation and inhibition of local immune responses in affected tissues during prolonged chronic infections is important for host protection. There is ample evidence that regulatory, tolerogenic dendritic cells (DC) are developed and present in tissues and inhibit overwhelming inflammatory reactions. Also, it was firmly established that stromal microenvironment of many organs is able to induce development of immature regulatory DC (DCreg), an essential element of a general immune regulatory network. However, direct experimental data demonstrating inhibition of immune responses by stroma-instructed immature DCreg in infectious models are scarce, and virtually nothing is known about functioning of this axis of immunity during tuberculosis (TB) infection. In this study, we demonstrate that lung stromal cells are capable of supporting the development in culture of immature CD11b(+)CD11c(low)CD103(-) DCreg from lineage-negative (lin(-)) bone marrow precursors. DCreg developed on lung stroma isolated from mice of genetically TB-hyper-susceptible I/St and relatively resistant B6 inbred strains inhibited proliferative response of mycobacteria-specific CD4(+) T-cell lines a dose-dependent manner. Importantly, the inhibitory activity of B6 DCreg was substantially higher than that of I/St Dcreg. Moreover, when the donors of stromal cells were chronically infected with virulent mycobacteria, the capacity to instruct inhibitory DCreg was retained in B6, but further diminished in I/St stromal cells. DCreg-provided suppression was mediated by a few soluble mediators, including PGE2, NO and IL-10. The content of CD4(+)Foxp3(+) Treg cells in the mediastinal, lung-draining lymph nodes at the advanced stages of chronic infection did not change in I/St, but increased 2-fold in B6 mice, and lung pathology was much more pronounced in the former mice. Taken together, these data provide genetic evidence that the capacity to maintain populations of regulatory cells during M. tuberculosis infection is a part of the host protective strategy.
authors: Laboratory for Immunogenetics, Central Institute for Tuberculosis, Moscow, Russia.
authors: Marina A
authors: MA
authors: Kapina
authors: Elvira I
authors: EI
authors: Rubakova
authors: Konstantin B
authors: KB
authors: Majorov
authors: Nadezhda N
authors: NN
authors: Logunova
authors: Alexander S
authors: AS
authors: Apt
mesh_terms: D000336:Aerosols; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D002448:Cell Adhesion; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D008168:Lung / Q000473:pathology*; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D018655:Lymphocyte Count; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D010641:Phenotype; D012995:Solubility; D017154:Stromal Cells / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000382:microbiology; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology*
chemical_list: D000336:Aerosols; D000942:Antigens, Bacterial
references: Immunol Rev. 2010 Mar;234(1):268-81
references: 20193025
references: Cell Microbiol. 2006 Feb;8(2):218-32
references: 16441433
references: Annu Rev Immunol. 2003;21:685-711
references: 12615891
references: Adv Immunol. 2010;108:111-65
references: 21056730
references: Curr Opin Immunol. 2009 Aug;21(4):378-84
references: 19646851
references: Curr Opin Microbiol. 2012 Feb;15(1):63-70
references: 22074861
references: Blood. 2006 Aug 15;108(4):1189-97
references: 16627758
references: Infect Immun. 2003 Feb;71(2):697-707
references: 12540548
references: Trends Immunol. 2002 Sep;23(9):445-9
references: 12200066
references: PLoS One. 2010 May 06;5(5):e10515
references: 20463893
references: J Immunol. 2011 Jun 15;186(12):7098-109
references: 21576507
references: Int J Tuberc Lung Dis. 2012 Nov;16(11):1424-32
references: 23044443
references: Infect Immun. 2012 Mar;80(3):1128-39
references: 22215739
references: Clin Exp Immunol. 1998 Feb;111(2):316-24
references: 9486398
references: Blood. 2003 Jun 15;101(12):4862-9
references: 12543858
references: Trends Immunol. 2005 Mar;26(3):123-9
references: 15745853
references: Methods Mol Biol. 2010;595:249-63
references: 19941118
references: Tuberculosis (Edinb). 2008 Nov;88(6):576-85
references: 18667358
references: Stem Cells. 2010 Mar 31;28(3):620-32
references: 20073041
references: Cell Microbiol. 2008 Dec;10(12):2589-604
references: 18771558
references: J Immunol Methods. 1991 May 17;139(1):107-14
references: 1904084
references: J Immunol. 2002 Jan 15;168(2):689-95
references: 11777962
references: Immunology. 1991 Dec;74(4):645-51
references: 1783423
references: Nat Rev Microbiol. 2007 Jan;5(1):39-47
references: 17160001
references: Immunity. 2004 Dec;21(6):805-16
references: 15589169
references: Trends Immunol. 2011 Feb;32(2):66-72
references: 21216195
references: Nat Immunol. 2005 May;6(5):507-14
references: 15821737
references: Cytokine. 2012 Sep;59(3):451-9
references: 22795953
references: Trends Immunol. 2006 Dec;27(12):580-7
references: 17049923
references: Nat Immunol. 2004 Nov;5(11):1124-33
references: 15475957
references: J Exp Med. 2011 May 9;208(5):885-91
references: 21536741
references: Front Immunol. 2012 Aug 21;3:262
references: 22934098
references: Eur J Immunol. 2008 Oct;38(10):2751-61
references: 18825748
references: Immunity. 2008 Sep 19;29(3):362-71
references: 18799144
references: PLoS Pathog. 2012;8(5):e1002607
references: 22589713