Suboptimal Activation of Antigen-Specific CD4
Effector Cells Enables Persistence of In
Vivo
Adaptive immunity to Mycobacterium tuberculosis controls
progressive bacterial growth and disease but does not eradicate infection. Among
CD4+ T cells in the lungs of M.
tuberculosis-infected mice, we observed that few produced IFN-γ
without ex vivo restimulation. Therefore, we hypothesized that one mechanism
whereby M. tuberculosis avoids elimination is by limiting
activation of CD4+ effector T cells at the site of infection in
the lungs. To test this hypothesis, we adoptively transferred Th1-polarized
CD4+ effector T cells specific for M.
tuberculosis Ag85B peptide 25 (P25TCRTh1 cells), which trafficked
to the lungs of infected mice and exhibited antigen-dependent IFN-γ
production. During the early phase of infection, ∼10% of P25TCRTh1
cells produced IFN-γ in vivo; this declined to <1% as infection
progressed to chronic phase. Bacterial downregulation of fbpB
(encoding Ag85B) contributed to the decrease in effector T cell activation in
the lungs, as a strain of M. tuberculosis engineered to express
fbpB in the chronic phase stimulated P25TCRTh1 effector
cells at higher frequencies in vivo, and this resulted in CD4+ T
cell-dependent reduction of lung bacterial burdens and prolonged survival of
mice. Administration of synthetic peptide 25 alone also increased activation of
endogenous antigen-specific effector cells and reduced the bacterial burden in
the lungs without apparent host toxicity. These results indicate that
CD4+ effector T cells are activated at suboptimal
frequencies in tuberculosis, and that increasing effector T cell activation in
the lungs by providing one or more epitope peptides may be a successful strategy
for TB therapy.
Vyšlo v časopise:
Suboptimal Activation of Antigen-Specific CD4
Effector Cells Enables Persistence of In
Vivo. PLoS Pathog 7(5): e32767. doi:10.1371/journal.ppat.1002063
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1002063
Souhrn
Adaptive immunity to Mycobacterium tuberculosis controls
progressive bacterial growth and disease but does not eradicate infection. Among
CD4+ T cells in the lungs of M.
tuberculosis-infected mice, we observed that few produced IFN-γ
without ex vivo restimulation. Therefore, we hypothesized that one mechanism
whereby M. tuberculosis avoids elimination is by limiting
activation of CD4+ effector T cells at the site of infection in
the lungs. To test this hypothesis, we adoptively transferred Th1-polarized
CD4+ effector T cells specific for M.
tuberculosis Ag85B peptide 25 (P25TCRTh1 cells), which trafficked
to the lungs of infected mice and exhibited antigen-dependent IFN-γ
production. During the early phase of infection, ∼10% of P25TCRTh1
cells produced IFN-γ in vivo; this declined to <1% as infection
progressed to chronic phase. Bacterial downregulation of fbpB
(encoding Ag85B) contributed to the decrease in effector T cell activation in
the lungs, as a strain of M. tuberculosis engineered to express
fbpB in the chronic phase stimulated P25TCRTh1 effector
cells at higher frequencies in vivo, and this resulted in CD4+ T
cell-dependent reduction of lung bacterial burdens and prolonged survival of
mice. Administration of synthetic peptide 25 alone also increased activation of
endogenous antigen-specific effector cells and reduced the bacterial burden in
the lungs without apparent host toxicity. These results indicate that
CD4+ effector T cells are activated at suboptimal
frequencies in tuberculosis, and that increasing effector T cell activation in
the lungs by providing one or more epitope peptides may be a successful strategy
for TB therapy.
Zdroje
1. World Health Organization
2010
Global tuberculosis control 2010
Geneva, Switzerland
WHO
2. WolfAJDesvignesLLinasBBanaieeNTamuraT
2008
Initiation of the adaptive immune response to Mycobacterium
tuberculosis depends on antigen production in the local lymph node, not the
lungs.
J Exp Med
205
105
115
3. CooperAM
2009
T cells in mycobacterial infection and disease.
Curr Opin Immunol
21
378
384
4. ReileyWWCalayagMDWittmerSTHuntingtonJLPearlJE
2008
ESAT-6-specific CD4 T cell responses to aerosol Mycobacterium
tuberculosis infection are initiated in the mediastinal lymph
nodes.
Proc Natl Acad Sci U S A
105
10961
10966
5. FlynnJLGoldsteinMMChanJTrieboldKJPfefferK
1995
Tumor necrosis factor-alpha is required in the protective immune
response against Mycobacterium tuberculosis in mice.
Immunity
2
561
572
6. WangooASparerTBrownINSnewinVAJanssenR
2001
Contribution of Th1 and Th2 cells to protection and pathology in
experimental models of granulomatous lung disease.
J Immunol
166
3432
3439
7. ChenXZhangMLiaoMGranerMWWuC
2009
Reduced Th17 response in patients with tuberculosis correlates
with IL-6R expression on CD4+ T Cells.
Am J Respir Crit Care Med
181
734
742
8. BaenaAPorcelliSA
2009
Evasion and subversion of antigen presentation by Mycobacterium
tuberculosis.
Tissue Antigens
74
189
204
9. DivangahiMDesjardinsDNunes-AlvesCRemoldHGBeharSM
2010
Eicosanoid pathways regulate adaptive immunity to Mycobacterium
tuberculosis.
Nat Immunol
11
751
758
10. HardingCVBoomWH
2010
Regulation of antigen presentation by Mycobacterium tuberculosis:
a role for Toll-like receptors.
Nat Rev Microbiol
8
296
307
11. Scott-BrowneJPShafianiSTucker-HeardGIshida-TsubotaKFontenotJD
2007
Expansion and function of Foxp3-expressing T regulatory cells
during tuberculosis.
J Exp Med
204
2159
2169
12. TurnerJGonzalez-JuarreroMEllisDLBasarabaRJKipnisA
2002
In vivo IL-10 production reactivates chronic pulmonary
tuberculosis in C57BL/6 mice.
J Immunol
169
6343
6351
13. YiJSCoxMAZajacAJ
2010
T-cell exhaustion: characteristics, causes and
conversion.
Immunology
129
474
481
14. ReileyWWShafianiSWittmerSTTucker-HeardGMoonJJ
2010
Distinct functions of antigen-specific CD4 T cells during murine
Mycobacterium tuberculosis infection.
Proc Natl Acad Sci U S A
107
19408
19413
15. TingLMKimACCattamanchiAErnstJD
1999
Mycobacterium tuberculosis inhibits IFN-gamma transcriptional
responses without inhibiting activation of STAT1.
J Immunol
163
3898
3906
16. BanaieeNKincaidEZBuchwaldUJacobsWRJrErnstJD
2006
Potent inhibition of macrophage responses to IFN-gamma by live
virulent Mycobacterium tuberculosis is independent of mature mycobacterial
lipoproteins but dependent on TLR2.
J Immunol
176
3019
3027
17. PaiRKConveryMHamiltonTABoomWHHardingCV
2003
Inhibition of IFN-gamma-induced class II transactivator
expression by a 19-kDa lipoprotein from Mycobacterium tuberculosis: a
potential mechanism for immune evasion.
J Immunol
171
175
184
18. RohdeKYatesRMPurdyGERussellDG
2007
Mycobacterium tuberculosis and the environment within the
phagosome.
Immunol Rev
219
37
54
19. ClemensDLHorwitzMA
1995
Characterization of the Mycobacterium tuberculosis phagosome and
evidence that phagosomal maturation is inhibited.
J Exp Med
181
257
270
20. HincheyJLeeSJeonBYBasarabaRJVenkataswamyMM
2007
Enhanced priming of adaptive immunity by a proapoptotic mutant of
Mycobacterium tuberculosis.
J Clin Invest
117
2279
2288
21. MillerJLVelmuruganKCowanMJBrikenV
2010
The type I NADH dehydrogenase of Mycobacterium tuberculosis
counters phagosomal NOX2 activity to inhibit TNF-alpha-mediated host cell
apoptosis.
PLoS Pathog
6
e1000864
22. VelmuruganKChenBMillerJLAzogueSGursesS
2007
Mycobacterium tuberculosis nuoG is a virulence gene that inhibits
apoptosis of infected host cells.
PLoS Pathog
3
e110
23. NossEHPaiRKSellatiTJRadolfJDBelisleJ
2001
Toll-like receptor 2-dependent inhibition of macrophage class II
MHC expression and antigen processing by 19-kDa lipoprotein of Mycobacterium
tuberculosis.
J Immunol
167
910
918
24. SinghCRMoultonRAArmitigeLYBidaniASnuggsM
2006
Processing and presentation of a mycobacterial antigen 85B
epitope by murine macrophages is dependent on the phagosomal acquisition of
vacuolar proton ATPase and in situ activation of cathepsin
D.
J Immunol
177
3250
3259
25. HmamaZGabathulerRJefferiesWAde JongGReinerNE
1998
Attenuation of HLA-DR expression by mononuclear phagocytes
infected with Mycobacterium tuberculosis is related to intracellular
sequestration of immature class II heterodimers.
J Immunol
161
4882
4893
26. PancholiPMirzaABhardwajNSteinmanRM
1993
Sequestration from immune CD4+ T cells of mycobacteria
growing in human macrophages.
Science
260
984
986
27. HuffordMMKimTSSunJBracialeTJ
2010
Antiviral CD8+ T cell effector activities in situ are
regulated by target cell type.
J Exp Med
208
167
180
28. LiuFWhittonJL
2005
Cutting edge: re-evaluating the in vivo cytokine responses of
CD8+ T cells during primary and secondary viral
infections.
J Immunol
174
5936
5940
29. AbeRVandenberghePCraigheadNSmootDSLeeKP
1995
Distinct signal transduction in mouse CD4+ and CD8+
splenic T cells after CD28 receptor ligation.
J Immunol
154
985
997
30. SunSZhangXToughDFSprentJ
1998
Type I interferon-mediated stimulation of T cells by CpG
DNA.
J Exp Med
188
2335
2342
31. LahnMKalataradiHMittelstadtPPflumEVollmerM
1998
Early preferential stimulation of gamma delta T cells by
TNF-alpha.
J Immunol
160
5221
5230
32. YanagisawaSKoikeMKariyoneANagaiSTakatsuK
1997
Mapping of V beta 11+ helper T cell epitopes on
mycobacterial antigen in mouse primed with Mycobacterium
tuberculosis.
Int Immunol
9
227
237
33. JungYJRyanLLaCourseRNorthRJ
2005
Properties and protective value of the secondary versus primary T
helper type 1 response to airborne Mycobacterium tuberculosis infection in
mice.
J Exp Med
201
1915
1924
34. BuchTHeppnerFLTertiltCHeinenTJKremerM
2005
A Cre-inducible diphtheria toxin receptor mediates cell lineage
ablation after toxin administration.
Nat Methods
2
419
426
35. McLachlanJBCatronDMMoonJJJenkinsMK
2009
Dendritic cell antigen presentation drives simultaneous cytokine
production by effector and regulatory T cells in inflamed
skin.
Immunity
30
277
288
36. CummingsLABarrettSLWilkersonWDFellnerovaICooksonBT
2005
FliC-specific CD4+ T cell responses are restricted by
bacterial regulation of antigen expression.
J Immunol
174
7929
7938
37. BanaieeNJacobsWRJrErnstJD
2006
Regulation of Mycobacterium tuberculosis whiB3 in the mouse lung
and macrophages.
Infect Immun
74
6449
6457
38. ShiLJungYJTyagiSGennaroMLNorthRJ
2003
Expression of Th1-mediated immunity in mouse lungs induces a
Mycobacterium tuberculosis transcription pattern characteristic of
nonreplicating persistence.
Proc Natl Acad Sci U S A
100
241
246
39. MoguesTGoodrichMERyanLLaCourseRNorthRJ
2001
The relative importance of T cell subsets in immunity and
immunopathology of airborne Mycobacterium tuberculosis infection in
mice.
J Exp Med
193
271
280
40. JungYJLaCourseRRyanLNorthRJ
2002
Virulent but not avirulent Mycobacterium tuberculosis can evade
the growth inhibitory action of a T helper 1-dependent, nitric oxide
Synthase 2-independent defense in mice.
J Exp Med
196
991
998
41. MahonRNRojasREFultonSAFrankoJLHardingCV
2009
Mycobacterium tuberculosis cell wall glycolipids directly inhibit
CD4+ T-cell activation by interfering with proximal T-cell-receptor
signaling.
Infect Immun
77
4574
4583
42. ShafianiSTucker-HeardGKariyoneATakatsuKUrdahlKB
2010
Pathogen-specific regulatory T cells delay the arrival of
effector T cells in the lung during early tuberculosis.
J Exp Med
207
1409
1420
43. RedfordPSBoonstraAReadSPittJGrahamC
2010
Enhanced protection to Mycobacterium tuberculosis infection in
IL-10-deficient mice is accompanied by early and enhanced Th1 responses in
the lung.
Eur J Immunol
40
2200
2210
44. Filipe-SantosOPescherPBreartBLippunerCAebischerT
2009
A dynamic map of antigen recognition by CD4 T cells at the site
of Leishmania major infection.
Cell Host Microbe
6
23
33
45. RogersonBJJungYJLaCourseRRyanLEnrightN
2006
Expression levels of Mycobacterium tuberculosis antigen-encoding
genes versus production levels of antigen-specific T cells during stationary
level lung infection in mice.
Immunology
118
195
201
46. BarkerLFBrennanMJRosensteinPKSadoffJC
2009
Tuberculosis vaccine research: the impact of
immunology.
Curr Opin Immunol
21
331
338
47. StewartGRSnewinVAWalzlGHussellTTormayP
2001
Overexpression of heat-shock proteins reduces survival of
Mycobacterium tuberculosis in the chronic phase of
infection.
Nat Med
7
732
737
48. OholYMGoetzDHChanKShilohMUCraikCS
2010
Mycobacterium tuberculosis MycP1 protease plays a dual role in
regulation of ESX-1 secretion and virulence.
Cell Host Microbe
7
210
220
49. JagannathCLindseyDRDhandayuthapaniSXuYHunterRLJr
2009
Autophagy enhances the efficacy of BCG vaccine by increasing
peptide presentation in mouse dendritic cells.
Nat Med
15
267
276
50. GehringAJDobosKMBelisleJTHardingCVBoomWH
2004
Mycobacterium tuberculosis LprG (Rv1411c): a novel TLR-2 ligand
that inhibits human macrophage class II MHC antigen
processing.
J Immunol
173
2660
2668
51. PecoraNDGehringAJCanadayDHBoomWHHardingCV
2006
Mycobacterium tuberculosis LprA is a lipoprotein agonist of TLR2
that regulates innate immunity and APC function.
J Immunol
177
422
429
52. KincaidEZErnstJD
2003
Mycobacterium tuberculosis exerts gene-selective inhibition of
transcriptional responses to IFN-gamma without inhibiting STAT1
function.
J Immunol
171
2042
2049
53. FortuneSMSolacheAJaegerAHillPJBelisleJT
2004
Mycobacterium tuberculosis inhibits macrophage responses to
IFN-gamma through myeloid differentiation factor 88-dependent and
-independent mechanisms.
J Immunol
172
6272
6280
54. KincaidEZWolfAJDesvignesLMahapatraSCrickDC
2007
Codominance of TLR2-dependent and TLR2-independent modulation of
MHC class II in Mycobacterium tuberculosis infection in
vivo.
J Immunol
179
3187
3195
55. PecoraNDFultonSARebaSMDrageMGSimmonsDP
2009
Mycobacterium bovis BCG decreases MHC-II expression in vivo on
murine lung macrophages and dendritic cells during aerosol
infection.
Cell Immunol
254
94
104
56. GallegosAMPamerEGGlickmanMS
2008
Delayed protection by ESAT-6-specific effector CD4+ T cells
after airborne M. tuberculosis infection.
J Exp Med
205
2359
2368
57. ChiangCYRileyLW
2005
Exogenous reinfection in tuberculosis.
Lancet Infect Dis
5
629
636
58. KitamuraHSedlikCJacquetAZaragozaBDusseauxM
2010
Long peptide vaccination can lead to lethality through CD4+
T cell-mediated cytokine storm.
J Immunol
185
892
901
59. LiuFFeuerRHassettDEWhittonJL
2006
Peptide vaccination of mice immune to LCMV or vaccinia virus
causes serious CD8 T cell-mediated, TNF-dependent
immunopathology.
J Clin Invest
116
465
475
60. BarberDLMayer-BarberKDFengCGSharpeAHSherA
2011
CD4 T cells promote rather than control tuberculosis in the
absence of PD-1-mediated inhibition.
J Immunol
186
1598
1607
61. TamuraTArigaHKinashiTUeharaSKikuchiT
2004
The role of antigenic peptide in CD4+ T helper phenotype
development in a T cell receptor transgenic model.
Int Immunol
16
1691
1699
62. WolfAJLinasBTrevejo-NunezGJKincaidETamuraT
2007
Mycobacterium tuberculosis infects dendritic cells with high
frequency and impairs their function in vivo.
J Immunol
179
2509
2519
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