Decrease of Foxp3+ Treg Cell Number and Acquisition of Effector Cell Phenotype During Lethal Infection

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2009 Nov 10

PMID 19896394

Citations 350

Authors

Guillaume Oldenhove

Nicolas Bouladoux

Elizabeth A Wohlfert

Jason A Hall

David Chou

Liliane Dos Santos

Shaun OBrien

Rebecca Blank

Erika Lamb

Sundar Natarajan

Robin Kastenmayer

Christopher Hunter

Michael E Grigg

Yasmine Belkaid

Affiliations

Soon will be listed here.

Abstract

Using a model of lethal oral infection with Toxoplasma gondii, we examined the fate of both induced and natural regulatory T (Treg) cells in the face of strong inflammatory responses occurring in a tolerogenic-prone environment. We found that during highly T helper 1 (Th1) cell-polarized mucosal immune responses, Treg cell numbers collapsed via multiple pathways, including blockade of Treg cell induction and disruption of endogenous Treg cell homeostasis. In particular, shutdown of interleukin 2 (IL-2) in the highly Th1 cell-polarized environment triggered by infection directly contributes to Treg cell incapacity to suppress effector responses and eventually leads to immunopathogenesis. Furthermore, we found that environmental cues provided by both local dendritic cells and effector T cells can induce the expression of T-bet transcription factor and IFN-gamma by Treg cells. These data reveal a mechanism for Th1 cell pathogenicity that extends beyond their proinflammatory program to limit Treg cell survival.

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References

Mennechet F, Kasper L, Rachinel N, Li W, Vandewalle A, Buzoni-Gatel D . Lamina propria CD4+ T lymphocytes synergize with murine intestinal epithelial cells to enhance proinflammatory response against an intracellular pathogen. J Immunol. 2002; 168(6):2988-96. DOI: 10.4049/jimmunol.168.6.2988. View

Sun C, Hall J, Blank R, Bouladoux N, Oukka M, Rodrigo Mora J . Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med. 2007; 204(8):1775-85. PMC: 2118682. DOI: 10.1084/jem.20070602. View

Sawitzki B, Kingsley C, Oliveira V, Karim M, Herber M, Wood K . IFN-gamma production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo. J Exp Med. 2005; 201(12):1925-35. PMC: 2212028. DOI: 10.1084/jem.20050419. View

Villarino A, Tato C, Stumhofer J, Yao Z, Cui Y, Hennighausen L . Helper T cell IL-2 production is limited by negative feedback and STAT-dependent cytokine signals. J Exp Med. 2007; 204(1):65-71. PMC: 2118423. DOI: 10.1084/jem.20061198. View

Dunay I, DaMatta R, Fux B, Presti R, Greco S, Colonna M . Gr1(+) inflammatory monocytes are required for mucosal resistance to the pathogen Toxoplasma gondii. Immunity. 2008; 29(2):306-17. PMC: 2605393. DOI: 10.1016/j.immuni.2008.05.019. View

Pfefferkorn E, PFEFFERKORN L . Toxoplasma gondii: isolation and preliminary characterization of temperature-sensitive mutants. Exp Parasitol. 1976; 39(3):365-76. DOI: 10.1016/0014-4894(76)90040-0. View

Coombes J, Siddiqui K, Arancibia-Carcamo C, Hall J, Sun C, Belkaid Y . A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med. 2007; 204(8):1757-64. PMC: 2118683. DOI: 10.1084/jem.20070590. View

Bettelli E, Carrier Y, Gao W, Korn T, Strom T, Oukka M . Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006; 441(7090):235-8. DOI: 10.1038/nature04753. View

Veldhoen M, Hocking R, Atkins C, Locksley R, Stockinger B . TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006; 24(2):179-89. DOI: 10.1016/j.immuni.2006.01.001. View

10.

Wilson E, Wille-Reece U, Dzierszinski F, Hunter C . A critical role for IL-10 in limiting inflammation during toxoplasmic encephalitis. J Neuroimmunol. 2005; 165(1-2):63-74. DOI: 10.1016/j.jneuroim.2005.04.018. View

11.

Jacobson N, Szabo S, Guler M, Gorham J, Murphy K . Regulation of interleukin-12 signalling during T helper phenotype development. Adv Exp Med Biol. 1996; 409:61-73. DOI: 10.1007/978-1-4615-5855-2_9. View

12.

Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig M, von Boehmer H . Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol. 2005; 6(12):1219-27. DOI: 10.1038/ni1265. View

13.

Zhou X, Bailey-Bucktrout S, Jeker L, Penaranda C, Martinez-Llordella M, Ashby M . Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol. 2009; 10(9):1000-7. PMC: 2729804. DOI: 10.1038/ni.1774. View

14.

Mucida D, Kutchukhidze N, Erazo A, Russo M, Lafaille J, Curotto de Lafaille M . Oral tolerance in the absence of naturally occurring Tregs. J Clin Invest. 2005; 115(7):1923-33. PMC: 1142115. DOI: 10.1172/JCI24487. View

15.

Duarte J, Zelenay S, Bergman M, Martins A, Demengeot J . Natural Treg cells spontaneously differentiate into pathogenic helper cells in lymphopenic conditions. Eur J Immunol. 2009; 39(4):948-55. DOI: 10.1002/eji.200839196. View

16.

Zheng Y, Chaudhry A, Kas A, deRoos P, Kim J, Chu T . Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature. 2009; 458(7236):351-6. PMC: 2864791. DOI: 10.1038/nature07674. View

17.

Roos D, Donald R, Morrissette N, Moulton A . Molecular tools for genetic dissection of the protozoan parasite Toxoplasma gondii. Methods Cell Biol. 1994; 45:27-63. DOI: 10.1016/s0091-679x(08)61845-2. View

18.

Denning T, Wang Y, Patel S, Williams I, Pulendran B . Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat Immunol. 2007; 8(10):1086-94. DOI: 10.1038/ni1511. View

19.

Stock P, Akbari O, Berry G, Freeman G, DeKruyff R, Umetsu D . Induction of T helper type 1-like regulatory cells that express Foxp3 and protect against airway hyper-reactivity. Nat Immunol. 2004; 5(11):1149-56. DOI: 10.1038/ni1122. View

20.

OMalley J, Sehra S, Thieu V, Yu Q, Chang H, Stritesky G . Signal transducer and activator of transcription 4 limits the development of adaptive regulatory T cells. Immunology. 2009; 127(4):587-95. PMC: 2729536. DOI: 10.1111/j.1365-2567.2008.03037.x. View