title: Interferon γ and Tumor Necrosis Factor Are Not Essential Parameters of CD4+ T-Cell Responses for Vaccine Control of Tuberculosis.
abstract: BACKGROUND
  Mycobacterium tuberculosis infects one third of the world's population and causes >8 million cases of tuberculosis annually. New vaccines are necessary to control the spread of tuberculosis. T cells, interferon γ (IFN-γ), and tumor necrosis factor (TNF) are necessary to control M. tuberculosis infection in both humans and unvaccinated experimental animal models. However, the immune responses necessary for vaccine efficacy against M. tuberculosis have not been defined. The multifunctional activity of T-helper type 1 (TH1) cells that simultaneously produce IFN-γ and TNF has been proposed as a candidate mechanism of vaccine efficacy.
  
  
  METHODS
  We used a mouse model of T-cell transfer and aerosolized M. tuberculosis infection to assess the contributions of TNF, IFN-γ, and inducible nitric oxide synthase (iNOS) to vaccine efficacy.
  
  
  RESULTS
  CD4(+) T cells were necessary and sufficient to transfer protection against aerosolized M. tuberculosis, but neither CD4(+) T cell-produced TNF nor host cell responsiveness to IFN-γ were necessary. Transfer of Tnf(-/-) CD4(+) T cells from vaccinated donors to Ifngr(-/-) recipients was also sufficient to confer protection. Activation of iNOS to produce reactive nitrogen species was not necessary for vaccine efficacy.
  
  
  CONCLUSIONS
  Induction of TH1 cells that coexpress IFN-γ and TNF is not a requirement for vaccine efficacy against M. tuberculosis, despite these cytokines being essential for control of M. tuberculosis in nonvaccinated animals.
authors: Infectious Disease Research Institute Department of Global Health, University of Washington, Seattle.
authors: Mark T
authors: MT
authors: Orr
authors: Infectious Disease Research Institute.
authors: Hillarie Plessner
authors: HP
authors: Windish
authors: Infectious Disease Research Institute.
authors: Elyse A
authors: EA
authors: Beebe
authors: Infectious Disease Research Institute.
authors: David
authors: D
authors: Argilla
authors: Infectious Disease Research Institute.
authors: Po-Wei D
authors: PW
authors: Huang
authors: Infectious Disease Research Institute.
authors: Valerie A
authors: VA
authors: Reese
authors: Infectious Disease Research Institute Department of Global Health, University of Washington, Seattle.
authors: Steven G
authors: SG
authors: Reed
authors: Infectious Disease Research Institute Department of Global Health, University of Washington, Seattle.
authors: Rhea N
authors: RN
authors: Coler
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D052247:Nitric Oxide Synthase Type II / Q000276:immunology; D053722:Receptors, Interleukin-17 / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology* / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000276:immunology* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D053722:Receptors, Interleukin-17; D032581:Tuberculosis Vaccines; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
keywords: ID93+GLA-SE; IFN-γ; Mycobacterium tuberculosis; TH1; TNF; vaccine
references: J Control Release. 2013 Nov 28;172(1):190-200
references: 23933525
references: Immunity. 1995 Jun;2(6):561-72
references: 7540941
references: Sci Transl Med. 2010 Oct 13;2(53):53ra74
references: 20944089
references: J Exp Med. 2011 Oct 24;208(11):2251-62
references: 21967766
references: J Exp Med. 2001 Aug 20;194(4):519-27
references: 11514607
references: Clin Transl Immunology. 2015 Apr 10;4(4):e35
references: 26175894
references: Infect Immun. 2005 Jan;73(1):666-70
references: 15618214
references: Tuberculosis (Edinb). 2012 Sep;92(5):422-33
references: 22738879
references: Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10338-43
references: 10468609
references: J Immunol. 2009 Jun 15;182(12):8047-55
references: 19494330
references: Nat Med. 2007 Jul;13(7):843-50
references: 17558415
references: J Exp Med. 2000 Aug 7;192(3):347-58
references: 10934223
references: Infect Immun. 2006 Apr;74(4):2128-37
references: 16552042
references: Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12434-9
references: 17640915
references: Am J Respir Crit Care Med. 2010 Oct 15;182(8):1073-9
references: 20558627
references: J Immunol. 2012 Jun 15;188(12):6205-15
references: 22566567
references: J Exp Med. 1993 Dec 1;178(6):2243-7
references: 8245795
references: Tuberculosis (Edinb). 2008 Jan;88(1):7-20
references: 17928269
references: J Immunol. 2013 Jan 1;190(1):270-7
references: 23233724
references: J Immunol. 2014 Sep 15;193(6):2911-8
references: 25086172
references: Nat Rev Microbiol. 2014 Apr;12(4):289-99
references: 24590243
references: Infect Immun. 2001 Dec;69(12):7711-7
references: 11705952
references: Arthritis Rheum. 2010 Feb;62(2):340-50
references: 20112395
references: PLoS Pathog. 2011 May;7(5):e1002052
references: 21625591
references: N Engl J Med. 2001 Oct 11;345(15):1098-104
references: 11596589
references: Immunity. 2009 Dec 18;31(6):974-85
references: 20064452
references: J Immunol. 2003 Nov 1;171(9):4689-99
references: 14568944
references: J Immunol. 2008 Dec 1;181(11):7948-57
references: 19017986
references: Immunity. 2011 Dec 23;35(6):1023-34
references: 22195750
references: Tuberculosis (Edinb). 2007 Nov;87(6):465-73
references: 17719276
references: J Leukoc Biol. 2005 Jun;77(6):914-22
references: 15767289
references: Annu Rev Genomics Hum Genet. 2007;8:163-92
references: 17492906
references: J Infect Dis. 2007 Jun 1;195(11):1643-50
references: 17471434
references: J Immunol. 2013 Sep 1;191(5):2514-25
references: 23904160
references: Lancet. 2013 Mar 23;381(9871):1021-8
references: 23391465
references: J Immunol. 2013 Jun 15;190(12):6311-9
references: 23677471
references: Infect Immun. 1997 Nov;65(11):4843-9
references: 9353074
references: Nat Genet. 1999 Apr;21(4):370-8
references: 10192386
references: Lancet. 2014 Sep 13;384(9947):1005-70
references: 25059949
references: Lancet. 2004 Dec 11-17;364(9451):2113-21
references: 15589309
references: J Immunol. 2008 Oct 1;181(7):4955-64
references: 18802099
references: J Exp Med. 1993 Dec 1;178(6):2249-54
references: 7504064
references: Annu Rev Immunol. 2009;27:393-422
references: 19302046
references: Eur J Immunol. 2007 Nov;37(11):3089-100
references: 17948267
references: Nat Immunol. 2007 Apr;8(4):369-77
references: 17351619
references: Semin Immunol. 2006 Dec;18(6):347-61
references: 16997570
references: Annu Rev Immunol. 2010;28:445-89
references: 20192806