title: Inducible CD4+LAP+Foxp3- regulatory T cells suppress allergic inflammation.
abstract: Regulatory T cells (Tregs) play a critical role in the maintenance of airway tolerance. We report that inhaled soluble Ag induces adaptive Foxp3(+) Tregs, as well as a regulatory population of CD4(+) T cells in the lungs and lung-draining lymph nodes that express latency-associated peptide (LAP) on their cell surface but do not express Foxp3. Blocking the cytokine IL-10 or TGF-β prevented the generation of LAP(+) Tregs and Foxp3(+) Tregs in vivo, and the LAP(+) Tregs could also be generated concomitantly with Foxp3(+) Tregs in vitro by culturing naive CD4(+) T cells with Ag and exogenous TGF-β. The LAP(+) Tregs strongly suppressed naive CD4(+) T cell proliferation, and transfer of sorted OVA-specific LAP(+) Tregs in vivo inhibited allergic eosinophilia and Th2 cytokine expression in the lung, either when present at the time of Th2 sensitization or when injected after Th2 cells were formed. Furthermore, inflammatory innate stimuli from house dust mite extract, nucleotide-binding oligomerization domain containing 2 ligand, and LPS, which are sufficient for blocking airway tolerance, strongly decreased the induction of LAP(+) Tregs. Taken together, we concluded that inducible Ag-specific LAP(+) Tregs can suppress asthmatic lung inflammation and constitute a mediator of airway tolerance together with Foxp3(+) Tregs.
authors.affiliation: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, CA 920370, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Duan
authors.forename: Takanori
authors.initials: T
authors.lastname: So
authors.forename: Amit K
authors.initials: AK
authors.lastname: Mehta
authors.forename: Heonsik
authors.initials: H
authors.lastname: Choi
authors.forename: Michael
authors.initials: M
authors.lastname: Croft
mesh_terms: D000485:Allergens / Q000008:administration & dosage / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000172:deficiency* / Q000235:genetics; D017930:Genes, Reporter; D007108:Immune Tolerance / Q000235:genetics; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000502:physiology; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000485:Allergens; D018984:Epitopes, T-Lymphocyte; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053773:Transforming Growth Factor beta1; D010047:Ovalbumin
references.citation: J Immunol. 2007 Jun 15;178(12):8081-9
references.pmid: 17548646
references.citation: PLoS One. 2010 Nov 24;5(11):e15523
references.pmid: 21124798
references.citation: Clin Exp Allergy. 2008 Feb;38(2):291-7
references.pmid: 18070166
references.citation: Immunity. 2007 Oct;27(4):635-46
references.pmid: 17919943
references.citation: Nat Immunol. 2004 Nov;5(11):1149-56
references.pmid: 15448689
references.citation: Cancer Immunol Immunother. 2010 Jun;59(6):819-28
references.pmid: 20012605
references.citation: Trends Immunol. 2005 Mar;26(3):136-40
references.pmid: 15745855
references.citation: Immunity. 2009 Sep 18;31(3):438-49
references.pmid: 19766086
references.citation: J Clin Invest. 2006 Apr;116(4):996-1004
references.pmid: 16543950
references.citation: J Immunol. 2002 Feb 1;168(3):1069-79
references.pmid: 11801640
references.citation: J Neurol Sci. 2008 Nov 15;274(1-2):9-12
references.pmid: 18804221
references.citation: J Allergy Clin Immunol. 2004 Dec;114(6):1425-33
references.pmid: 15577848
references.citation: Nat Med. 2002 Sep;8(9):1024-32
references.pmid: 12145647
references.citation: J Immunol. 2010 May 1;184(9):4620-4
references.pmid: 20368276
references.citation: J Immunol. 2009 Nov 15;183(10):6346-58
references.pmid: 19841178
references.citation: PLoS One. 2010 Aug 13;5(8):e12154
references.pmid: 20730048
references.citation: J Allergy Clin Immunol. 2010 Dec;126(6):1284-93.e10
references.pmid: 21051079
references.citation: Blood. 2006 Jan 15;107(2):619-27
references.pmid: 16179372
references.citation: Blood. 2009 May 21;113(21):5125-33
references.pmid: 19299332
references.citation: J Allergy Clin Immunol. 2008 Jun;121(6):1467-72, 1472.e1
references.pmid: 18423565
references.citation: Am J Respir Crit Care Med. 2009 Nov 15;180(10):936-47
references.pmid: 19696440
references.citation: Nat Immunol. 2001 Aug;2(8):725-31
references.pmid: 11477409
references.citation: J Cell Biol. 2007 Mar 12;176(6):787-93
references.pmid: 17353357
references.citation: Nat Med. 2006 Jun;12(6):627-35
references.pmid: 16715091
references.citation: Diabetes. 2007 Aug;56(8):2103-9
references.pmid: 17456848
references.citation: Curr Opin Cell Biol. 1994 Oct;6(5):726-33
references.pmid: 7530464
references.citation: J Immunol. 2009 Aug 15;183(4):2232-41
references.pmid: 19635906
references.citation: J Biol Chem. 2001 Apr 13;276(15):11469-72
references.pmid: 11278244
references.citation: J Immunol. 2005 Mar 15;174(6):3237-46
references.pmid: 15749854
references.citation: Proc Natl Acad Sci U S A. 2010 May 25;107(21):9765-70
references.pmid: 20445103
references.citation: J Immunol. 2007 Jul 15;179(2):744-7
references.pmid: 17617562
references.citation: J Immunol. 1999 Sep 1;163(5):2592-600
references.pmid: 10452998
references.citation: Blood. 1995 Oct 1;86(7):2672-8
references.pmid: 7545465
references.citation: Eur J Immunol. 2003 Sep;33(9):2419-28
references.pmid: 12938218
references.citation: J Clin Invest. 2004 Jul;114(1):28-38
references.pmid: 15232609
references.citation: PLoS One. 2008 Apr 02;3(4):e1914
references.pmid: 18392110
references.citation: J Immunol. 2010 Sep 15;185(6):3529-35
references.pmid: 20720212
references.citation: J Immunol. 2009 Jan 1;182(1):111-20
references.pmid: 19109141
references.citation: Immunity. 2006 Sep;25(3):455-71
references.pmid: 16973386
references.citation: J Immunol. 2004 Jan 15;172(2):834-42
references.pmid: 14707053
references.citation: Nat Rev Immunol. 2005 Apr;5(4):271-83
references.pmid: 15775993
references.citation: Infect Immun. 2010 Oct;78(10):4392-401
references.pmid: 20643858
references.citation: J Immunol. 2005 Feb 15;174(4):1783-6
references.pmid: 15699103
references.citation: J Exp Med. 2005 Dec 5;202(11):1539-47
references.pmid: 16314435
references.citation: J Immunol. 2010 Sep 15;185(6):3401-7
references.pmid: 20720210
references.citation: J Immunol. 2007 Feb 1;178(3):1433-42
references.pmid: 17237391
references.citation: Immunity. 2006 Sep;25(3):441-54
references.pmid: 16973387
references.citation: J Immunol. 2008 Dec 15;181(12):8650-9
references.pmid: 19050285
references.citation: J Immunol. 2004 Nov 15;173(10):6384-92
references.pmid: 15528378
references.citation: J Immunol. 2008 Jun 1;180(11):7327-37
references.pmid: 18490732
references.citation: J Exp Med. 2008 Sep 1;205(9):1975-81
references.pmid: 18710931