title: Lung-resident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance.
abstract: Airway tolerance is the usual outcome of inhalation of harmless antigens. Although T cell deletion and anergy are likely components of tolerogenic mechanisms in the lung, increasing evidence indicates that antigen-specific regulatory T cells (inducible Treg cells [iTreg cells]) that express Foxp3 are also critical. Several lung antigen-presenting cells have been suggested to contribute to tolerance, including alveolar macrophages (MØs), classical dendritic cells (DCs), and plasmacytoid DCs, but whether these possess the attributes required to directly promote the development of Foxp3(+) iTreg cells is unclear. Here, we show that lung-resident tissue MØs coexpress TGF-β and retinal dehydrogenases (RALDH1 and RALDH 2) under steady-state conditions and that their sampling of harmless airborne antigen and presentation to antigen-specific CD4 T cells resulted in the generation of Foxp3(+) Treg cells. Treg cell induction in this model depended on both TGF-β and retinoic acid. Transfer of the antigen-pulsed tissue MØs into the airways correspondingly prevented the development of asthmatic lung inflammation upon subsequent challenge with antigen. Moreover, exposure of lung tissue MØs to allergens suppressed their ability to generate iTreg cells coincident with blocking airway tolerance. Suppression of Treg cell generation required proteases and TLR-mediated signals. Therefore, lung-resident tissue MØs have regulatory functions, and strategies to target these cells might hold promise for prevention or treatment of allergic asthma.
authors.affiliation: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Pejman
authors.initials: P
authors.lastname: Soroosh
authors.forename: Taylor A
authors.initials: TA
authors.lastname: Doherty
authors.forename: Wei
authors.initials: W
authors.lastname: Duan
authors.forename: Amit Kumar
authors.initials: AK
authors.lastname: Mehta
authors.forename: Heonsik
authors.initials: H
authors.lastname: Choi
authors.forename: Yan Fei
authors.initials: YF
authors.lastname: Adams
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Mikulski
authors.forename: Naseem
authors.initials: N
authors.lastname: Khorram
authors.forename: Peter
authors.initials: P
authors.lastname: Rosenthal
authors.forename: David H
authors.initials: DH
authors.lastname: Broide
authors.forename: Michael
authors.initials: M
authors.lastname: Croft
mesh_terms: D000485:Allergens / Q000276:immunology / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D005260:Female; D007108:Immune Tolerance; D008168:Lung / Q000276:immunology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D000485:Allergens; D000970:Antineoplastic Agents; D051193:Toll-Like Receptors; D016212:Transforming Growth Factor beta; D014212:Tretinoin
references.citation: Nat Med. 2009 Apr;15(4):410-6
references.pmid: 19330007
references.citation: Curr Opin Immunol. 2006 Dec;18(6):738-44
references.pmid: 17023149
references.citation: Nat Immunol. 2001 Aug;2(8):725-31
references.pmid: 11477409
references.citation: J Clin Invest. 2001 Aug;108(4):577-83
references.pmid: 11518731
references.citation: Adv Exp Med Biol. 1993;329:305-10
references.pmid: 8379386
references.citation: Chest. 2007 Sep;132(3):1007-14
references.pmid: 17873195
references.citation: Nat Rev Immunol. 2005 Apr;5(4):271-83
references.pmid: 15775993
references.citation: Immunity. 2011 Feb 25;34(2):237-46
references.pmid: 21333554
references.citation: J Immunol. 2009 Aug 1;183(3):1732-8
references.pmid: 19592651
references.citation: Cytometry A. 2004 Oct;61(2):170-77
references.pmid: 15382026
references.citation: J Immunol. 2011 Jul 15;187(2):733-47
references.pmid: 21666057
references.citation: J Exp Med. 2004 Jul 5;200(1):89-98
references.pmid: 15238608
references.citation: Mucosal Immunol. 2012 Jan;5(1):53-65
references.pmid: 22012243
references.citation: J Allergy Clin Immunol. 2010 Dec;126(6):1284-93.e10
references.pmid: 21051079
references.citation: J Clin Invest. 2005 Jul;115(7):1923-33
references.pmid: 15937545
references.citation: Curr Opin Immunol. 2007 Dec;19(6):676-80
references.pmid: 17720466
references.citation: Nature. 2012 Feb 08;482(7385):395-9
references.pmid: 22318520
references.citation: J Immunol Methods. 2007 Oct 31;327(1-2):63-74
references.pmid: 17716680
references.citation: Clin Mol Allergy. 2006 Mar 28;4:5
references.pmid: 16569217
references.citation: J Exp Med. 1993 Jun 1;177(6):1773-7
references.pmid: 8496690
references.citation: Reg Immunol. 1993 May-Aug;5(3-4):151-7
references.pmid: 8240933
references.citation: J Immunol. 2007 Feb 1;178(3):1882-95
references.pmid: 17237439
references.citation: Exp Mol Med. 2011 May 31;43(5):275-80
references.pmid: 21415590
references.citation: Am J Respir Cell Mol Biol. 2011 Feb;44(2):127-33
references.pmid: 20525803
references.citation: Nat Immunol. 2007 Oct;8(10):1086-94
references.pmid: 17873879
references.citation: Nature. 2009 Jan 29;457(7229):585-8
references.pmid: 19060881
references.citation: Immunity. 2008 Jul 18;29(1):114-26
references.pmid: 18617425
references.citation: J Immunol. 2010 Feb 1;184(3):1317-27
references.pmid: 20042584
references.citation: Br J Haematol. 2004 May;125(3):392-9
references.pmid: 15086422
references.citation: J Exp Med. 2007 Aug 6;204(8):1775-85
references.pmid: 17620362
references.citation: J Immunol. 2009 Aug 1;183(3):1983-9
references.pmid: 19620319
references.citation: Nature. 2010 Feb 11;463(7282):808-12
references.pmid: 20072126
references.citation: Nat Immunol. 2008 Feb;9(2):194-202
references.pmid: 18157133
references.citation: Immunity. 2009 Sep 18;31(3):438-49
references.pmid: 19766086
references.citation: Eur J Immunol. 2006 Jun;36(6):1423-33
references.pmid: 16708400
references.citation: J Immunol. 1999 Sep 1;163(5):2592-600
references.pmid: 10452998
references.citation: Immunology. 1995 Jan;84(1):142-7
references.pmid: 7534261
references.citation: Immunity. 1998 Jul;9(1):59-70
references.pmid: 9697836
references.citation: J Exp Med. 2007 Aug 6;204(8):1765-74
references.pmid: 17620363
references.citation: J Clin Invest. 2005 Feb;115(2):313-25
references.pmid: 15668741
references.citation: J Clin Invest. 2004 Jul;114(1):28-38
references.pmid: 15232609
references.citation: Curr Pharm Des. 2012;18(27):4093-102
references.pmid: 22630084
references.citation: Curr Opin Immunol. 2006 Dec;18(6):727-32
references.pmid: 17010591
references.citation: J Immunol. 2011 Dec 15;187(12):6499-507
references.pmid: 22079987
references.citation: J Leukoc Biol. 1993 Apr;53(4):366-71
references.pmid: 8482916
references.citation: Science. 2007 Jul 13;317(5835):256-60
references.pmid: 17569825
references.citation: Am J Respir Cell Mol Biol. 2001 Sep;25(3):326-34
references.pmid: 11588010
references.citation: J Immunol. 2005 Nov 15;175(10):6900-8
references.pmid: 16272349
references.citation: PLoS One. 2010 Jun 04;5(6):e10973
references.pmid: 20532047
references.citation: J Exp Med. 2003 Dec 15;198(12):1875-86
references.pmid: 14676299
references.citation: J Immunol. 2008 Dec 15;181(12):8650-9
references.pmid: 19050285
references.citation: J Allergy Clin Immunol. 2001 Feb;107(2):258-64
references.pmid: 11174191
references.citation: Clin Exp Allergy. 1992 Dec;22(12):1107-14
references.pmid: 1486539
references.citation: J Exp Med. 2007 Aug 6;204(8):1757-64
references.pmid: 17620361
references.citation: J Exp Med. 2012 Jul 30;209(8):1505-17
references.pmid: 22802353
references.citation: Am J Respir Cell Mol Biol. 2012 Feb;46(2):165-72
references.pmid: 21908266
references.citation: Immunol Cell Biol. 2010 Aug;88(6):658-66
references.pmid: 20195280
references.citation: J Immunol. 2006 Nov 15;177(10):7346-54
references.pmid: 17082654
references.citation: Respir Res. 2009 Jan 16;10:2
references.pmid: 19149869
references.citation: J Biol Chem. 2002 Oct 18;277(42):39320-6
references.pmid: 12171914
references.citation: J Exp Med. 1993 Feb 1;177(2):397-407
references.pmid: 8426110
references.citation: Eur J Immunol. 2000 Nov;30(11):3207-18
references.pmid: 11093136
references.citation: Immunology. 1996 Feb;87(2):250-8
references.pmid: 8698387
references.citation: J Immunol. 2002 Nov 15;169(10):5904-11
references.pmid: 12421974