title: Fatal Leishmaniasis in the Absence of TNF Despite a Strong Th1 Response.
abstract: Induction of inducible nitric oxide synthase in mononuclear phagocytes by IFN-γ and innate tumor necrosis factor (TNF) provide the basis for an effective immune response to the intracellular parasite Leishmania (L.) major. In previous experiments, we observed a fatal visceral form of leishmaniasis in L. major-infected C57BL/6 TNF(-/-) mice. To further delineate the protective function of TNF and its receptor requirements, we comparatively assessed L. major-infected C57BL/6 mice that were either deficient for membrane and soluble TNF (Tnf (-) (/) (-)), for soluble TNF alone (memTnf(Δ/Δ) ), or the TNF receptors type 1 (Tnfr1 (-) (/) (-)) or type 2 (Tnfr2 (-) (/) (-)). We detected locally and systemically increased levels of the cytokine IFN-γ in the absence of the TNF-TNFR1-signaling pathway. An analysis of transcription factors and cytokines revealed that activated Tnf (-) (/) (-) CD4(+) T cells displayed a highly active Th1 phenotype with a strong usage of the T cell receptor Vβ5.1/2. From these data we conclude that the fatal outcome of L. major infection in Tnf (-) (/) (-) mice does not result from a skewed or deficient Th1 differentiation.
authors.affiliation: Comparative Genomics Centre, James Cook University, Townsville QN, Australia.
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Fromm
authors.affiliation: Menzies Institute for Medical Research Tasmania, HobartTAS, Australia; Blumenthal Group, The University of Queensland Diamantina Institute, Translational Research Institute, WoolloongabbaQLD, Australia.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Kling
authors.affiliation: Menzies Institute for Medical Research Tasmania, Hobart TAS, Australia.
authors.forename: Annika
authors.initials: A
authors.lastname: Remke
authors.affiliation: Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Friederich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen Erlangen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Bogdan
authors.affiliation: Menzies Institute for Medical Research Tasmania, Hobart TAS, Australia.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Körner
keywords: IFN-γ; T cell subtypes; cutaneous leishmaniasis; mouse models; tumor necrosis factor
references.citation: Immunity. 1997 May;6(5):541-9
references.pmid: 9175832
references.citation: Science. 2002 Jan 11;295(5553):338-42
references.pmid: 11786644
references.citation: Lancet Infect Dis. 2007 Sep;7(9):581-96
references.pmid: 17714672
references.citation: J Immunol. 1990 Dec 15;145(12):4306-10
references.pmid: 2175327
references.citation: J Immunol. 1998 Jun 1;160(11):5506-13
references.pmid: 9605154
references.citation: Infect Immun. 2003 Sep;71(9):5287-95
references.pmid: 12933876
references.citation: J Exp Med. 1990 Jan 1;171(1):115-27
references.pmid: 2104918
references.citation: J Biol Chem. 1997 Jun 6;272(23):14899-907
references.pmid: 9169460
references.citation: J Immunol. 1993 Jul 1;151(1):322-9
references.pmid: 7686939
references.citation: Eur J Immunol. 1997 Oct;27(10):2600-9
references.pmid: 9368616
references.citation: J Immunol. 1990 Dec 15;145(12):4290-7
references.pmid: 2124240
references.citation: J Exp Med. 1989 Jan 1;169(1):59-72
references.pmid: 2521244
references.citation: Cell Microbiol. 2008 Jun;10(6):1221-34
references.pmid: 18363880
references.citation: Parasite Immunol. 2007 Oct;29(10):501-13
references.pmid: 17883453
references.citation: Immunity. 1998 Jan;8(1):77-87
references.pmid: 9462513
references.citation: J Immunol. 1991 Nov 1;147(9):3149-55
references.pmid: 1833466
references.citation: Annu Rev Immunol. 1989;7:145-73
references.pmid: 2523712
references.citation: J Leukoc Biol. 1992 Mar;51(3):296-9
references.pmid: 1347312
references.citation: J Immunol. 2007 Jul 1;179(1):154-61
references.pmid: 17579033
references.citation: Microbes Infect. 2004 May;6(6):559-65
references.pmid: 15158189
references.citation: Front Immunol. 2012 Apr 17;3:80
references.pmid: 22566961
references.citation: J Immunol. 1992 Oct 15;149(8):2715-21
references.pmid: 1357029
references.citation: J Immunol. 1998 Mar 15;160(6):2560-4
references.pmid: 9510151
references.citation: J Leukoc Biol. 2004 Feb;75(2):163-89
references.pmid: 14525967
references.citation: Int J Parasitol. 2010 Jul;40(8):879-88
references.pmid: 20399786
references.citation: J Immunol. 1995 May 15;154(10):5320-30
references.pmid: 7730635
references.citation: Eur J Immunol. 2007 Dec;37(12):3424-34
references.pmid: 18034422
references.citation: J Immunol. 1998 Jan 15;160(2):943-52
references.pmid: 9551933
references.citation: J Exp Med. 1996 Apr 1;183(4):1501-14
references.pmid: 8666908
references.citation: Science. 1996 Jun 28;272(5270):1947-50
references.pmid: 8658169
references.citation: J Mol Biol. 1999 Jun 11;289(3):459-71
references.pmid: 10356322
references.citation: J Immunol. 2005 Mar 1;174(5):2934-41
references.pmid: 15728505
references.citation: FASEB J. 2014 Apr;28(4):1724-34
references.pmid: 24398292
references.citation: J Exp Med. 1994 Sep 1;180(3):783-93
references.pmid: 7520472
references.citation: Immunobiology. 2008;213(3-4):377-87
references.pmid: 18406382
references.citation: Genes Immun. 2004 Mar;5(2):93-100
references.pmid: 14668789
references.citation: Genes Immun. 2004 May;5(3):188-96
references.pmid: 14762398
references.citation: Eur J Immunol. 2008 Mar;38(3):720-31
references.pmid: 18266271
references.citation: Nat Immunol. 2005 Jun;6(6):600-7
references.pmid: 15852008
references.citation: J Immunol. 2006 Mar 15;176(6):3470-9
references.pmid: 16517715
references.citation: Eur J Immunol. 1988 Oct;18(10):1587-92
references.pmid: 3142779
references.citation: Infect Immun. 2010 Jun;78(6):2734-44
references.pmid: 20368343
references.citation: Microbes Infect. 2007 Sep;9(11):1260-6
references.pmid: 17890126
references.citation: J Exp Med. 1989 Dec 1;170(6):2097-104
references.pmid: 2584936
references.citation: J Immunol. 1986 Jul 15;137(2):702-7
references.pmid: 3487578
references.citation: Infect Immun. 2011 Jul;79(7):2699-708
references.pmid: 21518784
references.citation: Cell. 2000 Mar 17;100(6):655-69
references.pmid: 10761931
references.citation: J Immunol. 1989 Jul 1;143(1):266-74
references.pmid: 2499629
references.citation: Immunity. 2008 Jan;28(1):29-39
references.pmid: 18164222
references.citation: J Immunol. 2010 Jan 15;184(2):877-85
references.pmid: 20018611
references.citation: Cell. 1997 May 16;89(4):587-96
references.pmid: 9160750
references.citation: Immunity. 2001 Oct;15(4):533-43
references.pmid: 11672536
references.citation: Eur J Immunol. 2003 May;33(5):1224-34
references.pmid: 12731047
references.citation: Eur J Immunol. 1990 May;20(5):1131-5
references.pmid: 2113475
references.citation: Immunity. 2010 Jul 23;33(1):25-34
references.pmid: 20637660
references.citation: Trends Parasitol. 2008 Mar;24(3):135-42
references.pmid: 18262469
references.citation: Nat Rev Immunol. 2002 Nov;2(11):845-58
references.pmid: 12415308
references.citation: Blood. 2003 Oct 15;102(8):2724-7
references.pmid: 12816871
references.citation: Am J Trop Med Hyg. 1985 May;34(3):456-9
references.pmid: 4039899
references.citation: J Immunol. 1996 Jul 15;157(2):827-35
references.pmid: 8752935
references.citation: J Immunol. 2001 Mar 15;166(6):4012-9
references.pmid: 11238648