title: Multifunctional, high-level cytokine-producing Th1 cells in the lung, but not spleen, correlate with protection against Mycobacterium tuberculosis aerosol challenge in mice.
abstract: Boosting bacillus Calmette-Guérin (BCG)-primed mice with a recombinant adenovirus expressing Mycobacterium tuberculosis Ag 85A by different administration routes has very different effects on protection against aerosol challenge with M. tuberculosis. Mice boosted intradermally make very strong splenic CD4 and CD8 Th1 cytokine responses to Ag 85A, but show no change in lung mycobacterial burden over BCG primed animals. In contrast, intranasally boosted mice show greatly reduced mycobacterial burden and make a much weaker splenic response but a very strong lung CD4 and CD8 response to Ag 85A and an increased response to purified protein derivative. This effect is associated with the presence in the lung of multifunctional T cells, with high median fluorescence intensity and integrated median fluorescence intensity for IFN-gamma, IL-2, and TNF. In contrast, mice immunized with BCG alone have few Ag-specific cells in the lung and a low proportion of multifunctional cells, although individual cells have high median fluorescence intensity. Successful immunization regimes appear to induce Ag-specific cells with abundant intracellular cytokine staining.
authors.affiliation: The Jenner Institute, University of Oxford, Headington, Oxford, United Kingdom.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Forbes
authors.forename: Clare
authors.initials: C
authors.lastname: Sander
authors.forename: Edward O
authors.initials: EO
authors.lastname: Ronan
authors.forename: Helen
authors.initials: H
authors.lastname: McShane
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
authors.forename: Peter C L
authors.initials: PC
authors.lastname: Beverley
authors.forename: Elma Z
authors.initials: EZ
authors.lastname: Tchilian
mesh_terms: D000217:Acyltransferases / Q000008:administration & dosage / Q000276:immunology; D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology; D000281:Administration, Intranasal; D000336:Aerosols; D000595:Amino Acid Sequence; D000818:Animals; D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000276:immunology; D001500:BCG Vaccine / Q000008:administration & dosage / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis* / Q000502:physiology; D005260:Female; D006801:Humans; D007117:Immunization, Secondary / Q000379:methods; D007271:Injections, Intradermal; D008168:Lung / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009163:Mycobacterium bovis / Q000254:growth & development / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control*
chemical_list: D000336:Aerosols; D000942:Antigens, Bacterial; D001500:BCG Vaccine; D016207:Cytokines; D000217:Acyltransferases; C112580:antigen 85A, Mycobacterium tuberculosis
references.citation: Immunity. 2002 Feb;16(2):271-83
references.pmid: 11869687
references.citation: J Exp Med. 2001 Feb 5;193(3):271-80
references.pmid: 11157048
references.citation: J Immunol. 2003 Aug 1;171(3):1602-9
references.pmid: 12874255
references.citation: J Immunol. 2004 Apr 15;172(8):4875-82
references.pmid: 15067066
references.citation: J Immunol. 2004 Oct 1;173(7):4590-7
references.pmid: 15383593
references.citation: Epidemiol Infect. 1997 Feb;118(1):71-5
references.pmid: 9042037
references.citation: J Comp Pathol. 1998 Jul;119(1):27-44
references.pmid: 9717125
references.citation: J Immunol. 2004 Nov 15;173(10):6357-65
references.pmid: 15528375
references.citation: J Immunol. 2005 Jun 15;174(12):7986-94
references.pmid: 15944305
references.citation: J Clin Invest. 2005 Dec;115(12):3473-83
references.pmid: 16308575
references.citation: Vaccine. 2006 Apr 12;24(16):3353-64
references.pmid: 16488518
references.citation: Immunity. 2006 Apr;24(4):439-49
references.pmid: 16618602
references.citation: Eur J Immunol. 2006 May;36(5):1136-44
references.pmid: 16619288
references.citation: Vet Immunol Immunopathol. 2006 Jun 15;111(3-4):219-29
references.pmid: 16540176
references.citation: Trends Immunol. 2006 May;27(5):235-43
references.pmid: 16580261
references.citation: Blood. 2006 Jun 15;107(12):4781-9
references.pmid: 16467198
references.citation: Infect Immun. 2006 Aug;74(8):4634-43
references.pmid: 16861651
references.citation: J Immunol. 2007 Feb 15;178(4):2387-95
references.pmid: 17277145
references.citation: J Immunol. 2007 Mar 1;178(5):2661-5
references.pmid: 17312107
references.citation: J Biol Chem. 2007 Mar 2;282(9):6106-15
references.pmid: 17197446
references.citation: Nat Immunol. 2007 Apr;8(4):369-77
references.pmid: 17351619
references.citation: Cell Microbiol. 2007 Jun;9(6):1455-65
references.pmid: 17250590
references.citation: J Immunol. 2007 Jul 1;179(1):36-40
references.pmid: 17579018
references.citation: Nat Med. 2007 Jul;13(7):843-50
references.pmid: 17558415
references.citation: Infect Immun. 2007 Aug;75(8):4105-15
references.pmid: 17526747
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12434-9
references.pmid: 17640915
references.citation: J Clin Invest. 2007 Aug;117(8):2279-88
references.pmid: 17671656
references.citation: Immunology. 2007 Nov;122(3):316-25
references.pmid: 17521369
references.citation: J Virol. 2008 Apr;82(8):3822-33
references.pmid: 18256155
references.citation: Science. 2001 Mar 23;291(5512):2413-7
references.pmid: 11264538
references.citation: J Immunol. 2000 May 1;164(9):4853-60
references.pmid: 10779794
references.citation: J Infect Dis. 2002 Nov 15;186(10):1448-57
references.pmid: 12404160