A Gamma Interferon Independent Mechanism of CD4 T Cell Mediated
Control of Infection
CD4 T cell deficiency or defective IFNγ signaling render humans and mice
highly susceptible to Mycobacterium tuberculosis (Mtb)
infection. The prevailing model is that Th1 CD4 T cells produce IFNγ to
activate bactericidal effector mechanisms of infected macrophages. Here we test
this model by directly interrogating the effector functions of Th1 CD4 T cells
required to control Mtb in vivo. While Th1 CD4 T cells specific for the Mtb
antigen ESAT-6 restrict in vivo Mtb growth, this inhibition is independent of
IFNγ or TNF and does not require the perforin or FAS effector pathways.
Adoptive transfer of Th17 CD4 T cells specific for ESAT-6 partially inhibited
Mtb growth while Th2 CD4 T cells were largely ineffective. These results imply a
previously unrecognized IFNγ/TNF independent pathway that efficiently
controls Mtb and suggest that optimization of this alternative effector function
may provide new therapeutic avenues to combat Mtb through vaccination.
Vyšlo v časopise:
A Gamma Interferon Independent Mechanism of CD4 T Cell Mediated
Control of Infection. PLoS Pathog 7(5): e32767. doi:10.1371/journal.ppat.1002052
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1002052
Souhrn
CD4 T cell deficiency or defective IFNγ signaling render humans and mice
highly susceptible to Mycobacterium tuberculosis (Mtb)
infection. The prevailing model is that Th1 CD4 T cells produce IFNγ to
activate bactericidal effector mechanisms of infected macrophages. Here we test
this model by directly interrogating the effector functions of Th1 CD4 T cells
required to control Mtb in vivo. While Th1 CD4 T cells specific for the Mtb
antigen ESAT-6 restrict in vivo Mtb growth, this inhibition is independent of
IFNγ or TNF and does not require the perforin or FAS effector pathways.
Adoptive transfer of Th17 CD4 T cells specific for ESAT-6 partially inhibited
Mtb growth while Th2 CD4 T cells were largely ineffective. These results imply a
previously unrecognized IFNγ/TNF independent pathway that efficiently
controls Mtb and suggest that optimization of this alternative effector function
may provide new therapeutic avenues to combat Mtb through vaccination.
Zdroje
1. CooperAMDaltonDKStewartTAGriffinJPRussellDG
1993
Disseminated tuberculosis in interferon gamma gene-disrupted
mice.
J Exp Med
178
2243
2247
2. FlynnJLChanJTrieboldKJDaltonDKStewartTA
1993
An essential role for interferon gamma in resistance to
Mycobacterium tuberculosis infection.
J Exp Med
178
2249
2254
3. van de VosseEHoeveMAOttenhoffTH
2004
Human genetics of intracellular infectious diseases: molecular
and cellular immunity against mycobacteria and salmonellae.
Lancet Infect Dis
4
739
749
4. Filipe-SantosOBustamanteJChapgierAVogtGde BeaucoudreyL
2006
Inborn errors of IL-12/23- and IFN-gamma-mediated immunity:
molecular, cellular, and clinical features.
Semin Immunol
18
347
361
5. CarusoAMSerbinaNKleinETrieboldKBloomBR
1999
Mice deficient in CD4 T cells have only transiently diminished
levels of IFN-gamma, yet succumb to tuberculosis.
J Immunol
162
5407
5416
6. EhrtSSchnappingerDBekiranovSDrenkowJShiS
2001
Reprogramming of the macrophage transcriptome in response to
interferon-gamma and Mycobacterium tuberculosis: signaling roles of nitric
oxide synthase-2 and phagocyte oxidase.
J Exp Med
194
1123
1140
7. SatoKAkakiTTomiokaH
1998
Differential potentiation of anti-mycobacterial activity and
reactive nitrogen intermediate-producing ability of murine peritoneal
macrophages activated by interferon-gamma (IFN-gamma) and tumour necrosis
factor-alpha (TNF-alpha).
Clin Exp Immunol
112
63
68
8. MajlessiLSimsovaMJarvisZBrodinPRojasMJ
2006
An increase in antimycobacterial Th1-cell responses by
prime-boost protocols of immunization does not enhance protection against
tuberculosis.
Infect Immun
74
2128
2137
9. MittruckerHWSteinhoffUKohlerAKrauseMLazarD
2007
Poor correlation between BCG vaccination-induced T cell responses
and protection against tuberculosis.
Proc Natl Acad Sci U S A
104
12434
12439
10. LambertPHHawkridgeTHanekomWA
2009
New vaccines against tuberculosis.
Clin Chest Med
30
811
826
11. ScangaCAMohanVPYuKJosephHTanakaK
2000
Depletion of CD4(+) T cells causes reactivation of murine
persistent tuberculosis despite continued expression of interferon gamma and
nitric oxide synthase 2.
J Exp Med
192
347
358
12. KaginaBMAbelBScribaTJHughesEJKeyserA
2010
Specific T Cell Frequency and Cytokine Expression Profile do not
Correlate with Protection against Tuberculosis, Following BCG Vaccination of
Newborns.
Am J Respir Crit Care Med
182
1073
9
13. GallegosAMPamerEGGlickmanMS
2008
Delayed protection by ESAT-6-specific effector CD4+T cells
after airborne M. tuberculosis infection.
J Exp Med
205
2359
2368
14. ShilohMUNathanCF
2000
Reactive nitrogen intermediates and the pathogenesis of
Salmonella and mycobacteria.
Curr Opin Microbiol
3
35
42
15. LocksleyRMKilleenNLenardoMJ
2001
The TNF and TNF receptor superfamilies: integrating mammalian
biology.
Cell
104
487
501
16. FlynnJLGoldsteinMMChanJTrieboldKJPfefferK
1995
Tumor necrosis factor-alpha is required in the protective immune
response against Mycobacterium tuberculosis in mice.
Immunity
2
561
572
17. WoodworthJSWuYBeharSM
2008
Mycobacterium tuberculosis-specific CD8+T cells require
perforin to kill target cells and provide protection in
vivo.
J Immunol
181
8595
8603
18. LewinsohnDMBementTTXuJLynchDHGrabsteinKH
1998
Human purified protein derivative-specific CD4+T cells use
both CD95-dependent and CD95-independent cytolytic
mechanisms.
J Immunol
160
2374
2379
19. TurnerJD'SouzaCDPearlJEMariettaPNoelM
2001
CD8- and CD95/95L-dependent mechanisms of resistance in mice with
chronic pulmonary tuberculosis.
Am J Respir Cell Mol Biol
24
203
209
20. LohningMHegazyANPinschewerDDBusseDLangKS
2008
Long-lived virus-reactive memory T cells generated from purified
cytokine-secreting T helper type 1 and type 2 effectors.
J Exp Med
205
53
61
21. BadovinacVPHaringJSHartyJT
2007
Initial T cell receptor transgenic cell precursor frequency
dictates critical aspects of the CD8(+) T cell response to
infection.
Immunity
26
827
841
22. ReinerSL
2007
Development in motion: helper T cells at work.
Cell
129
33
36
23. KhaderSABellGKPearlJEFountainJJRangel-MorenoJ
2007
IL-23 and IL-17 in the establishment of protective pulmonary
CD4+T cell responses after vaccination and during Mycobacterium
tuberculosis challenge.
Nat Immunol
8
369
377
24. HartyJTBevanMJ
1995
Specific immunity to Listeria monocytogenes in the absence of IFN
gamma.
Immunity
3
109
117
25. CowleySCElkinsKL
2003
CD4+T cells mediate IFN-gamma-independent control of
Mycobacterium tuberculosis infection both in vitro and in
vivo.
J Immunol
171
4689
4699
26. StanleySARaghavanSHwangWWCoxJS
2003
Acute infection and macrophage subversion by Mycobacterium
tuberculosis require a specialized secretion system.
Proc Natl Acad Sci U S A
100
13001
13006
27. GuinnKMHickeyMJMathurSKZakelKLGrotzkeJE
2004
Individual RD1-region genes are required for export of
ESAT-6/CFP-10 and for virulence of Mycobacterium
tuberculosis.
Mol Microbiol
51
359
370
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
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