How Regulatory T Cells Work

Overview

Journal Nat Rev Immunol

Specialty Allergy & Immunology

Date 2008 Jun 21

PMID 18566595

Citations 1499

Authors

Dario A A Vignali

Lauren W Collison

Creg J Workman

Affiliations

Soon will be listed here.

Abstract

Regulatory T (T(Reg)) cells are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases. However, they also limit beneficial responses by suppressing sterilizing immunity and limiting antitumour immunity. Given that T(Reg) cells can have both beneficial and deleterious effects, there is considerable interest in determining their mechanisms of action. In this Review, we describe the basic mechanisms used by T(Reg) cells to mediate suppression and discuss whether one or many of these mechanisms are likely to be crucial for T(Reg)-cell function. In addition, we propose the hypothesis that effector T cells may not be 'innocent' parties in this suppressive process and might in fact potentiate T(Reg)-cell function.

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References

Bergmann C, Strauss L, Zeidler R, Lang S, Whiteside T . Expansion and characteristics of human T regulatory type 1 cells in co-cultures simulating tumor microenvironment. Cancer Immunol Immunother. 2007; 56(9):1429-42. PMC: 11031003. DOI: 10.1007/s00262-007-0280-9. View

Pyzik M, Piccirillo C . TGF-beta1 modulates Foxp3 expression and regulatory activity in distinct CD4+ T cell subsets. J Leukoc Biol. 2007; 82(2):335-46. DOI: 10.1189/jlb.1006644. View

Takahashi T, KUNIYASU Y, Toda M, Sakaguchi N, Itoh M, Iwata M . 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. 1999; 10(12):1969-80. DOI: 10.1093/intimm/10.12.1969. View

Rubtsov Y, Rasmussen J, Chi E, Fontenot J, Castelli L, Ye X . Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity. 2008; 28(4):546-58. DOI: 10.1016/j.immuni.2008.02.017. View

Loser K, Apelt J, Voskort M, Mohaupt M, Balkow S, Schwarz T . IL-10 controls ultraviolet-induced carcinogenesis in mice. J Immunol. 2007; 179(1):365-71. DOI: 10.4049/jimmunol.179.1.365. View

Shevach E . From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity. 2006; 25(2):195-201. DOI: 10.1016/j.immuni.2006.08.003. View

Morgan M, van Bilsen J, Bakker A, Heemskerk B, Schilham M, Hartgers F . Expression of FOXP3 mRNA is not confined to CD4+CD25+ T regulatory cells in humans. Hum Immunol. 2004; 66(1):13-20. DOI: 10.1016/j.humimm.2004.05.016. View

Yamaguchi T, Hirota K, Nagahama K, Ohkawa K, Takahashi T, Nomura T . Control of immune responses by antigen-specific regulatory T cells expressing the folate receptor. Immunity. 2007; 27(1):145-59. DOI: 10.1016/j.immuni.2007.04.017. View

Zhao D, Thornton A, DiPaolo R, Shevach E . Activated CD4+CD25+ T cells selectively kill B lymphocytes. Blood. 2006; 107(10):3925-32. PMC: 1895290. DOI: 10.1182/blood-2005-11-4502. View

10.

Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R . Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood. 2007; 110(4):1225-32. DOI: 10.1182/blood-2006-12-064527. View

11.

Deaglio S, Dwyer K, Gao W, Friedman D, Usheva A, Erat A . Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med. 2007; 204(6):1257-65. PMC: 2118603. DOI: 10.1084/jem.20062512. View

12.

Taams L, van Amelsfort J, Tiemessen M, Jacobs K, de Jong E, Akbar A . Modulation of monocyte/macrophage function by human CD4+CD25+ regulatory T cells. Hum Immunol. 2005; 66(3):222-30. PMC: 3904343. DOI: 10.1016/j.humimm.2004.12.006. View

13.

Houot R, Perrot I, Garcia E, Durand I, Lebecque S . Human CD4+CD25high regulatory T cells modulate myeloid but not plasmacytoid dendritic cells activation. J Immunol. 2006; 176(9):5293-8. DOI: 10.4049/jimmunol.176.9.5293. View

14.

Schambach F, Schupp M, Lazar M, Reiner S . Activation of retinoic acid receptor-alpha favours regulatory T cell induction at the expense of IL-17-secreting T helper cell differentiation. Eur J Immunol. 2007; 37(9):2396-9. DOI: 10.1002/eji.200737621. View

15.

Bennett C, Christie J, Ramsdell F, Brunkow M, Ferguson P, Whitesell L . The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001; 27(1):20-1. DOI: 10.1038/83713. View

16.

Fontenot J, Dooley J, Farr A, Rudensky A . Developmental regulation of Foxp3 expression during ontogeny. J Exp Med. 2005; 202(7):901-6. PMC: 2213175. DOI: 10.1084/jem.20050784. View

17.

Rouse B, Sarangi P, Suvas S . Regulatory T cells in virus infections. Immunol Rev. 2006; 212:272-86. DOI: 10.1111/j.0105-2896.2006.00412.x. View

18.

Thornton A, Shevach E . CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med. 1998; 188(2):287-96. PMC: 2212461. DOI: 10.1084/jem.188.2.287. View

19.

Molitor-Dart M, Andrassy J, Kwun J, Kayaoglu H, Roenneburg D, Haynes L . Developmental exposure to noninherited maternal antigens induces CD4+ T regulatory cells: relevance to mechanism of heart allograft tolerance. J Immunol. 2007; 179(10):6749-61. DOI: 10.4049/jimmunol.179.10.6749. View

20.

Cao X, Cai S, Fehniger T, Song J, Collins L, Piwnica-Worms D . Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity. 2007; 27(4):635-46. DOI: 10.1016/j.immuni.2007.08.014. View