Regulatory T Cell Suppressive Potency Dictates the Balance between Bacterial Proliferation and Clearance during Persistent Infection
The pathogenesis of persistent infection is dictated by the balance between opposing immune activation and suppression signals. Herein, virulent Salmonella was used to explore the role and potential importance of Foxp3-expressing regulatory T cells in dictating the natural progression of persistent bacterial infection. Two distinct phases of persistent Salmonella infection are identified. In the first 3–4 weeks after infection, progressively increasing bacterial burden was associated with delayed effector T cell activation. Reciprocally, at later time points after infection, reductions in bacterial burden were associated with robust effector T cell activation. Using Foxp3GFP reporter mice for ex vivo isolation of regulatory T cells, we demonstrate that the dichotomy in infection tempo between early and late time points is directly paralleled by drastic changes in Foxp3+ Treg suppressive potency. In complementary experiments using Foxp3DTR mice, the significance of these shifts in Treg suppressive potency on infection outcome was verified by enumerating the relative impacts of regulatory T cell ablation on bacterial burden and effector T cell activation at early and late time points during persistent Salmonella infection. Moreover, Treg expression of CTLA-4 directly paralleled changes in suppressive potency, and the relative effects of Treg ablation could be largely recapitulated by CTLA-4 in vivo blockade. Together, these results demonstrate that dynamic regulation of Treg suppressive potency dictates the course of persistent bacterial infection.
Vyšlo v časopise:
Regulatory T Cell Suppressive Potency Dictates the Balance between Bacterial Proliferation and Clearance during Persistent Infection. PLoS Pathog 6(8): e32767. doi:10.1371/journal.ppat.1001043
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1001043
Souhrn
The pathogenesis of persistent infection is dictated by the balance between opposing immune activation and suppression signals. Herein, virulent Salmonella was used to explore the role and potential importance of Foxp3-expressing regulatory T cells in dictating the natural progression of persistent bacterial infection. Two distinct phases of persistent Salmonella infection are identified. In the first 3–4 weeks after infection, progressively increasing bacterial burden was associated with delayed effector T cell activation. Reciprocally, at later time points after infection, reductions in bacterial burden were associated with robust effector T cell activation. Using Foxp3GFP reporter mice for ex vivo isolation of regulatory T cells, we demonstrate that the dichotomy in infection tempo between early and late time points is directly paralleled by drastic changes in Foxp3+ Treg suppressive potency. In complementary experiments using Foxp3DTR mice, the significance of these shifts in Treg suppressive potency on infection outcome was verified by enumerating the relative impacts of regulatory T cell ablation on bacterial burden and effector T cell activation at early and late time points during persistent Salmonella infection. Moreover, Treg expression of CTLA-4 directly paralleled changes in suppressive potency, and the relative effects of Treg ablation could be largely recapitulated by CTLA-4 in vivo blockade. Together, these results demonstrate that dynamic regulation of Treg suppressive potency dictates the course of persistent bacterial infection.
Zdroje
1. HornickRB
GreismanSE
WoodwardTE
DuPontHL
DawkinsAT
1970 Typhoid fever: pathogenesis and immunologic control. N Engl J Med 283 686 691
2. HornickRB
GreismanSE
WoodwardTE
DuPontHL
DawkinsAT
1970 Typhoid fever: pathogenesis and immunologic control. 2. N Engl J Med 283 739 746
3. MerrellDS
FalkowS
2004 Frontal and stealth attack strategies in microbial pathogenesis. Nature 430 250 256
4. ParryCM
HienTT
DouganG
WhiteNJ
FarrarJJ
2002 Typhoid fever. N Engl J Med 347 1770 1782
5. BhanMK
BahlR
BhatnagarS
2005 Typhoid and paratyphoid fever. Lancet 366 749 762
6. MonackDM
MuellerA
FalkowS
2004 Persistent bacterial infections: the interface of the pathogen and the host immune system. Nat Rev Microbiol 2 747 765
7. BelkaidY
2007 Regulatory T cells and infection: a dangerous necessity. Nat Rev Immunol 7 875 888
8. BelkaidY
TarbellK
2009 Regulatory T cells in the control of host-microorganism interactions (*). Annu Rev Immunol 27 551 589
9. SuvasS
RouseBT
2006 Treg control of antimicrobial T cell responses. Curr Opin Immunol 18 344 348
10. PetersN
SacksD
2006 Immune privilege in sites of chronic infection: Leishmania and regulatory T cells. Immunol Rev 213 159 179
11. MendezS
RecklingSK
PiccirilloCA
SacksD
BelkaidY
2004 Role for CD4(+) CD25(+) regulatory T cells in reactivation of persistent leishmaniasis and control of concomitant immunity. J Exp Med 200 201 210
12. BelkaidY
PiccirilloCA
MendezS
ShevachEM
SacksDL
2002 CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420 502 507
13. SuvasS
AzkurAK
KimBS
KumaraguruU
RouseBT
2004 CD4+CD25+ regulatory T cells control the severity of viral immunoinflammatory lesions. J Immunol 172 4123 4132
14. SuvasS
KumaraguruU
PackCD
LeeS
RouseBT
2003 CD4+CD25+ T cells regulate virus-specific primary and memory CD8+ T cell responses. J Exp Med 198 889 901
15. KursarM
KochM
MittruckerHW
NouaillesG
BonhagenK
2007 Cutting Edge: Regulatory T cells prevent efficient clearance of Mycobacterium tuberculosis. J Immunol 178 2661 2665
16. HesseM
PiccirilloCA
BelkaidY
PruferJ
Mentink-KaneM
2004 The pathogenesis of schistosomiasis is controlled by cooperating IL-10-producing innate effector and regulatory T cells. J Immunol 172 3157 3166
17. LongTT
NakazawaS
OnizukaS
HuamanMC
KanbaraH
2003 Influence of CD4+CD25+ T cells on Plasmodium berghei NK65 infection in BALB/c mice. Int J Parasitol 33 175 183
18. HisaedaH
MaekawaY
IwakawaD
OkadaH
HimenoK
2004 Escape of malaria parasites from host immunity requires CD4+ CD25+ regulatory T cells. Nat Med 10 29 30
19. UzonnaJE
WeiG
YurkowskiD
BretscherP
2001 Immune elimination of Leishmania major in mice: implications for immune memory, vaccination, and reactivation disease. J Immunol 167 6967 6974
20. HoriS
TakahashiT
SakaguchiS
2003 Control of autoimmunity by naturally arising regulatory CD4+ T cells. Adv Immunol 81 331 371
21. KhattriR
CoxT
YasaykoSA
RamsdellF
2003 An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 4 337 342
22. FontenotJD
GavinMA
RudenskyAY
2003 Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4 330 336
23. FontenotJD
RasmussenJP
WilliamsLM
DooleyJL
FarrAG
2005 Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22 329 341
24. KimJM
RasmussenJP
RudenskyAY
2007 Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 8 191 197
25. LundJM
HsingL
PhamTT
RudenskyAY
2008 Coordination of early protective immunity to viral infection by regulatory T cells. Science 320 1220 1224
26. LanteriMC
O'BrienKM
PurthaWE
CameronMJ
LundJM
2009 Tregs control the development of symptomatic West Nile virus infection in humans and mice. J Clin Invest 119 3266 3277
27. GruenheidS
GrosP
2000 Genetic susceptibility to intracellular infections: Nramp1, macrophage function and divalent cations transport. Curr Opin Microbiol 3 43 48
28. MaloD
VoganK
VidalS
HuJ
CellierM
1994 Haplotype mapping and sequence analysis of the mouse Nramp gene predict susceptibility to infection with intracellular parasites. Genomics 23 51 61
29. MonackDM
BouleyDM
FalkowS
2004 Salmonella typhimurium persists within macrophages in the mesenteric lymph nodes of chronically infected Nramp1+/+ mice and can be reactivated by IFNgamma neutralization. J Exp Med 199 231 241
30. MittruckerHW
KohlerA
KaufmannSH
2002 Characterization of the murine T-lymphocyte response to Salmonella enterica serovar Typhimurium infection. Infect Immun 70 199 203
31. NaucielC
1990 Role of CD4+ T cells and T-independent mechanisms in acquired resistance to Salmonella typhimurium infection. J Immunol 145 1265 1269
32. NaucielC
RoncoE
GuenetJL
PlaM
1988 Role of H-2 and non-H-2 genes in control of bacterial clearance from the spleen in Salmonella typhimurium-infected mice. Infect Immun 56 2407 2411
33. MittruckerHW
KaufmannSH
2000 Immune response to infection with Salmonella typhimurium in mice. J Leukoc Biol 67 457 463
34. CaramalhoI
Lopes-CarvalhoT
OstlerD
ZelenayS
HauryM
2003 Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide. J Exp Med 197 403 411
35. LiuH
Komai-KomaM
XuD
LiewFY
2006 Toll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells. Proc Natl Acad Sci U S A 103 7048 7053
36. CrellinNK
GarciaRV
HadisfarO
AllanSE
SteinerTS
2005 Human CD4+ T cells express TLR5 and its ligand flagellin enhances the suppressive capacity and expression of FOXP3 in CD4+CD25+ T regulatory cells. J Immunol 175 8051 8059
37. PengG
GuoZ
KiniwaY
VooKS
PengW
2005 Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science 309 1380 1384
38. SutmullerRP
den BrokMH
KramerM
BenninkEJ
ToonenLW
2006 Toll-like receptor 2 controls expansion and function of regulatory T cells. J Clin Invest 116 485 494
39. PasareC
MedzhitovR
2003 Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299 1033 1036
40. ThorntonAM
ShevachEM
1998 CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 188 287 296
41. TakahashiT
KuniyasuY
TodaM
SakaguchiN
ItohM
1998 Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int Immunol 10 1969 1980
42. PiccirilloCA
ShevachEM
2001 Cutting edge: control of CD8+ T cell activation by CD4+CD25+ immunoregulatory cells. J Immunol 167 1137 1140
43. LuuRA
GurnaniK
DudaniR
KammaraR
van FaassenH
2006 Delayed expansion and contraction of CD8+ T cell response during infection with virulent Salmonella typhimurium. J Immunol 177 1516 1525
44. MiyaraM
SakaguchiS
2007 Natural regulatory T cells: mechanisms of suppression. Trends Mol Med 13 108 116
45. VignaliDA
CollisonLW
WorkmanCJ
2008 How regulatory T cells work. Nat Rev Immunol 8 523 532
46. WingK
OnishiY
Prieto-MartinP
YamaguchiT
MiyaraM
2008 CTLA-4 control over Foxp3+ regulatory T cell function. Science 322 271 275
47. AssemanC
MauzeS
LeachMW
CoffmanRL
PowrieF
1999 An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med 190 995 1004
48. MarieJC
LetterioJJ
GavinM
RudenskyAY
2005 TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J Exp Med 201 1061 1067
49. NakamuraK
KitaniA
StroberW
2001 Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med 194 629 644
50. CaoX
CaiSF
FehnigerTA
SongJ
CollinsLI
2007 Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity 27 635 646
51. GotsmanI
GrabieN
GuptaR
DacostaR
MacConmaraM
2006 Impaired regulatory T-cell response and enhanced atherosclerosis in the absence of inducible costimulatory molecule. Circulation 114 2047 2055
52. KitazawaY
FujinoM
WangQ
KimuraH
AzumaM
2007 Involvement of the programmed death-1/programmed death-1 ligand pathway in CD4+CD25+ regulatory T-cell activity to suppress alloimmune responses. Transplantation 83 774 782
53. DeaglioS
DwyerKM
GaoW
FriedmanD
UshevaA
2007 Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 204 1257 1265
54. ShimizuJ
YamazakiS
TakahashiT
IshidaY
SakaguchiS
2002 Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 3 135 142
55. JiHB
LiaoG
FaubionWA
Abadia-MolinaAC
CozzoC
2004 Cutting edge: the natural ligand for glucocorticoid-induced TNF receptor-related protein abrogates regulatory T cell suppression. J Immunol 172 5823 5827
56. ValzasinaB
GuiducciC
DislichH
KilleenN
WeinbergAD
2005 Triggering of OX40 (CD134) on CD4(+)CD25+ T cells blocks their inhibitory activity: a novel regulatory role for OX40 and its comparison with GITR. Blood 105 2845 2851
57. SuffiaIJ
RecklingSK
PiccirilloCA
GoldszmidRS
BelkaidY
2006 Infected site-restricted Foxp3+ natural regulatory T cells are specific for microbial antigens. J Exp Med 203 777 788
58. TaylorJJ
MohrsM
PearceEJ
2006 Regulatory T cell responses develop in parallel to Th responses and control the magnitude and phenotype of the Th effector population. J Immunol 176 5839 5847
59. McKeeAS
PearceEJ
2004 CD25+CD4+ cells contribute to Th2 polarization during helminth infection by suppressing Th1 response development. J Immunol 173 1224 1231
60. McSorleySJ
CooksonBT
JenkinsMK
2000 Characterization of CD4+ T cell responses during natural infection with Salmonella typhimurium. J Immunol 164 986 993
61. MoonJJ
ChuHH
PepperM
McSorleySJ
JamesonSC
2007 Naive CD4(+) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity 27 203 213
62. McCoyK
CamberisM
GrosGL
1997 Protective immunity to nematode infection is induced by CTLA-4 blockade. J Exp Med 186 183 187
63. RoweJH
JohannsTM
ErteltJM
LaiJC
WaySS
2009 Cytotoxic T-lymphocyte antigen 4 blockade augments the T-cell response primed by attenuated Listeria monocytogenes resulting in more rapid clearance of virulent bacterial challenge. Immunology 128 e471 478
64. FurzeRC
CulleyFJ
SelkirkME
2006 Differential roles of the co-stimulatory molecules GITR and CTLA-4 in the immune response to Trichinella spiralis. Microbes Infect 8 2803 2810
65. Scott-BrowneJP
ShafianiS
Tucker-HeardG
Ishida-TsubotaK
FontenotJD
2007 Expansion and function of Foxp3-expressing T regulatory cells during tuberculosis. J Exp Med 204 2159 2169
66. HisaedaH
TetsutaniK
ImaiT
MoriyaC
TuL
2008 Malaria parasites require TLR9 signaling for immune evasion by activating regulatory T cells. J Immunol 180 2496 2503
67. RauschS
HuehnJ
KirchhoffD
RzepeckaJ
SchnoellerC
2008 Functional analysis of effector and regulatory T cells in a parasitic nematode infection. Infect Immun 76 1908 1919
68. BaumgartM
TompkinsF
LengJ
HesseM
2006 Naturally occurring CD4+Foxp3+ regulatory T cells are an essential, IL-10-independent part of the immunoregulatory network in Schistosoma mansoni egg-induced inflammation. J Immunol 176 5374 5387
69. ErteltJM
RoweJH
JohannsTM
LaiJC
McLachlanJB
2009 Selective priming and expansion of antigen-specific Foxp3− CD4+ T cells during Listeria monocytogenes infection. J Immunol 182 3032 3038
70. HsiehCS
ZhengY
LiangY
FontenotJD
RudenskyAY
2006 An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat Immunol 7 401 410
71. HsiehCS
LiangY
TyznikAJ
SelfSG
LiggittD
2004 Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 21 267 277
72. CozzoC
LermanMA
BoesteanuA
LarkinJ3rd
JordanMS
2005 Selection of CD4+CD25+ regulatory T cells by self-peptides. Curr Top Microbiol Immunol 293 3 23
73. KasowKA
ChenX
KnowlesJ
WichlanD
HandgretingerR
2004 Human CD4+CD25+ regulatory T cells share equally complex and comparable repertoires with CD4+CD25− counterparts. J Immunol 172 6123 6128
74. FazilleauN
BachelezH
GougeonML
ViguierM
2007 Cutting edge: size and diversity of CD4+CD25high Foxp3+ regulatory T cell repertoire in humans: evidence for similarities and partial overlapping with CD4+CD25− T cells. J Immunol 179 3412 3416
75. SakaguchiS
WingK
OnishiY
Prieto-MartinP
YamaguchiT
2009 Regulatory T cells: how do they suppress immune responses? Int Immunol 21 1105 1111
76. al-RamadiBK
ChenYW
MeisslerJJJr
EisensteinTK
1991 Immunosuppression induced by attenuated Salmonella. Reversal by IL-4. J Immunol 147 1954 1961
77. HoerttBE
OuJ
KopeckoDJ
BaronLS
WarrenRL
1989 Novel virulence properties of the Salmonella typhimurium virulence-associated plasmid: immune suppression and stimulation of splenomegaly. Plasmid 21 48 58
78. MacFarlaneAS
SchwachaMG
EisensteinTK
1999 In vivo blockage of nitric oxide with aminoguanidine inhibits immunosuppression induced by an attenuated strain of Salmonella typhimurium, potentiates Salmonella infection, and inhibits macrophage and polymorphonuclear leukocyte influx into the spleen. Infect Immun 67 891 898
79. MatsuiK
AraiT
1998 Salmonella infection-induced non-responsiveness of murine splenic T-lymphocytes to interleukin-2 (IL-2) involves inhibition of IL-2 receptor gamma chain expression. FEMS Immunol Med Microbiol 20 175 180
80. SrinivasanA
McSorleySJ
2007 Pivotal advance: exposure to LPS suppresses CD4+ T cell cytokine production in Salmonella-infected mice and exacerbates murine typhoid. J Leukoc Biol 81 403 411
81. FreudenbergMA
KumazawaY
MedingS
LanghorneJ
GalanosC
1991 Gamma interferon production in endotoxin-responder and -nonresponder mice during infection. Infect Immun 59 3484 3491
82. WeissDS
RaupachB
TakedaK
AkiraS
ZychlinskyA
2004 Toll-like receptors are temporally involved in host defense. J Immunol 172 4463 4469
83. Cervantes-BarraganL
Gil-CruzC
Pastelin-PalaciosR
LangKS
IsibasiA
2009 TLR2 and TLR4 signaling shapes specific antibody responses to Salmonella typhi antigens. Eur J Immunol 39 126 135
84. UematsuS
JangMH
ChevrierN
GuoZ
KumagaiY
2006 Detection of pathogenic intestinal bacteria by Toll-like receptor 5 on intestinal CD11c+ lamina propria cells. Nat Immunol 7 868 874
85. FeuilletV
MedjaneS
MondorI
DemariaO
PagniPP
2006 Involvement of Toll-like receptor 5 in the recognition of flagellated bacteria. Proc Natl Acad Sci U S A 103 12487 12492
86. MagnussonM
TobesR
SanchoJ
ParejaE
2007 Cutting edge: natural DNA repetitive extragenic sequences from gram-negative pathogens strongly stimulate TLR9. J Immunol 179 31 35
87. ForwardNA
FurlongSJ
YangY
LinTJ
HoskinDW
Signaling through TLR7 enhances the immunosuppressive activity of murine CD4+CD25+ T regulatory cells. J Leukoc Biol 87 117 125
88. JohannsTM
ErteltJM
LaiJC
RoweJH
AvantRA
2010 Naturally occurring altered peptide ligands control Salmonella-specific CD4+ T cell proliferation, IFN-gamma production, and protective potency. J Immunol 184 869 876
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
PLOS Pathogens
2010 Číslo 8
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
Najčítanejšie v tomto čísle
- Contribution of Coagulases towards Disease and Protective Immunity
- Early Severe Inflammatory Responses to Uropathogenic Predispose to Chronic and Recurrent Urinary Tract Infection
- The Transcription Factor Rbf1 Is the Master Regulator for -Mating Type Controlled Pathogenic Development in
- Immune Modulation with Sulfasalazine Attenuates Immunopathogenesis but Enhances Macrophage-Mediated Fungal Clearance during Pneumonia