How regulatory T cells work (original) (raw)

• Sakaguchi, S. et al. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol. Rev. 182, 18–32 (2001).
  Article CAS PubMed Google Scholar
• Shevach, E. M. et al. The lifestyle of naturally occurring CD4+ CD25+ Foxp3+ regulatory T cells. Immunol. Rev. 212, 60–73 (2006).
  Article CAS PubMed Google Scholar
• Xystrakis, E., Boswell, S. E. & Hawrylowicz, C. M. T regulatory cells and the control of allergic disease. Expert. Opin. Biol. Ther. 6, 121–133 (2006).
  Article CAS PubMed Google Scholar
• Coombes, J. L., Robinson, N. J., Maloy, K. J., Uhlig, H. H. & Powrie, F. Regulatory T cells and intestinal homeostasis. Immunol. Rev. 204, 184–194 (2005).
  Article CAS PubMed Google Scholar
• Belkaid, Y. Regulatory T cells and infection: a dangerous necessity. Nature Rev. Immunol. 7, 875–888 (2007).
  Article CAS Google Scholar
• Rouse, B. T., Sarangi, P. P. & Suvas, S. Regulatory T cells in virus infections. Immunol. Rev. 212, 272–286 (2006).
  Article CAS PubMed Google Scholar
• Kretschmer, K., Apostolou, I., Jaeckel, E., Khazaie, K. & von Boehmer, H. Making regulatory T cells with defined antigen specificity: role in autoimmunity and cancer. Immunol. Rev. 212, 163–169 (2006).
  Article CAS PubMed Google Scholar
• Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).
  Article CAS PubMed Google Scholar
• Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immunol. 4, 330–336 (2003). References 8 and 9 provided the first direct evidence that FOXP3 is required for T Reg -cell development and is sufficient to confer regulatory activity on naive T cells.
  Article CAS Google Scholar
• Bennett, C. L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nature Genet. 27, 20–21 (2001).
  Article CAS PubMed Google Scholar
• Wildin, R. S. et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nature Genet. 27, 18–20 (2001).
  Article CAS PubMed Google Scholar
• Brunkow, M. E. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nature Genet. 27, 68–73 (2001). References 10–12 were the first to identify FOXP3 as the defective gene in patients with IPEX and in scurfy mice.
  Article CAS PubMed Google Scholar
• Rudensky, A. Foxp3 and dominant tolerance. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 360, 1645–1646 (2005).
  Article PubMed PubMed Central Google Scholar
• Ramsdell, F. Foxp3 and natural regulatory T cells: key to a cell lineage? Immunity 19, 165–168 (2003).
  Article CAS PubMed Google Scholar
• Hill, J. A. et al. Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. Immunity 27, 786–800 (2007).
  Article CAS PubMed Google Scholar
• Allan, S. E. et al. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int. Immunol. 19, 345–354 (2007).
  Article CAS PubMed Google Scholar
• Morgan, M. E. et al. Expression of FOXP3 mRNA is not confined to CD4+CD25+ T regulatory cells in humans. Hum. Immunol. 66, 13–20 (2005).
  Article CAS PubMed Google Scholar
• Wang, J., Ioan-Facsinay, A., van der Voort, E. I., Huizinga, T. W. & Toes, R. E. Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur. J. Immunol. 37, 129–138 (2007).
  Article CAS PubMed Google Scholar
• Gavin, M. A. et al. Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development. Proc. Natl Acad. Sci. USA 103, 6659–6664 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Tran, D. Q., Ramsey, H. & Shevach, E. M. Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-β-dependent but does not confer a regulatory phenotype. Blood 110, 2983–2990 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Vignali, D. How many mechanisms do regulatory T cells need? Eur. J. Immunol. 38, 908–911 (2008).
  Article CAS PubMed Google Scholar
• Tang, Q. & Bluestone, J. A. The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nature Immunol. 9, 239–244 (2008).
  Article CAS Google Scholar
• Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164 (1995). This seminal paper re-ignited interest in 'suppressor' cells by demonstrating that a small CD4+CD25+ T-cell population had regulatory activity.
  CAS PubMed Google Scholar
• Shevach, E. M. From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity 25, 195–201 (2006).
  Article CAS PubMed Google Scholar
• Takahashi, T. et al. 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 (1998).
  Article CAS PubMed Google Scholar
• Thornton, A. M. & Shevach, E. M. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 188, 287–296 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Dieckmann, D., Plottner, H., Berchtold, S., Berger, T. & Schuler, G. Ex vivo isolation and characterization of CD4+CD25+ T cells with regulatory properties from human blood. J. Exp. Med. 193, 1303–1310 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Jonuleit, H. et al. Identification and functional characterization of human CD4+CD25+ T cells with regulatory properties isolated from peripheral blood. J. Exp. Med. 193, 1285–1294 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Hawrylowicz, C. M. & O'Garra, A. Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma. Nature Rev. Immunol. 5, 271–283 (2005).
  Article CAS Google Scholar
• Annacker, O., Asseman, C., Read, S. & Powrie, F. Interleukin-10 in the regulation of T cell-induced colitis. J. Autoimmun. 20, 277–279 (2003).
  Article CAS PubMed Google Scholar
• Joetham, A. et al. Naturally occurring lung CD4+CD25+ T cell regulation of airway allergic responses depends on IL-10 induction of TGF-β. J. Immunol. 178, 1433–1442 (2007).
  Article CAS PubMed Google Scholar
• Kearley, J., Barker, J. E., Robinson, D. S. & Lloyd, C. M. Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent. J. Exp. Med. 202, 1539–1547 (2005). This paper revealed the interesting distinction that IL-10 is required for the T Reg -cell-mediated control of airway hyper-reactivity but is derived from the suppressed effector T cells rather than the T Reg cells.
  Article CAS PubMed PubMed Central Google Scholar
• Rubtsov, Y. P. et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28, 546–558 (2008).
  Article CAS PubMed Google Scholar
• Stoop, J. N. et al. Tumor necrosis factor α inhibits the suppressive effect of regulatory T cells on the hepatitis B virus-specific immune response. Hepatology 46, 699–705 (2007).
  Article CAS PubMed Google Scholar
• Molitor-Dart, M. L. et al. Developmental exposure to noninherited maternal antigens induces CD4+ T regulatory cells: relevance to mechanism of heart allograft tolerance. J. Immunol. 179, 6749–6761 (2007).
  Article CAS PubMed Google Scholar
• Kursar, M. et al. Cutting Edge: regulatory T cells prevent efficient clearance of Mycobacterium tuberculosis. J. Immunol. 178, 2661–2665 (2007).
  Article CAS PubMed Google Scholar
• Jankovic, D. et al. Conventional T-bet+Foxp3− Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. J. Exp. Med. 204, 273–283 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Anderson, C. F., Oukka, M., Kuchroo, V. J. & Sacks, D. CD4+CD25−Foxp3−Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis. J. Exp. Med. 204, 285–297 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Beiting, D. P. et al. Coordinated control of immunity to muscle stage Trichinella spiralis by IL-10, regulatory T cells, and TGF-β. J. Immunol. 178, 1039–1047 (2007).
  Article CAS PubMed Google Scholar
• Asseman, C., Mauze, S., Leach, M. W., Coffman, R. L. & Powrie, F. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J. Exp. Med. 190, 995–1004 (1999). This paper demonstrated that T Reg cells require IL-10 for their maximal regulatory activity.
  Article CAS PubMed PubMed Central Google Scholar
• Bergmann, C., Strauss, L., Zeidler, R., Lang, S. & Whiteside, T. L. Expansion and characteristics of human T regulatory type 1 cells in co-cultures simulating tumor microenvironment. Cancer Immunol. Immunother. 56, 1429–1442 (2007).
  Article PubMed Google Scholar
• Loser, K. et al. IL-10 controls ultraviolet-induced carcinogenesis in mice. J. Immunol. 179, 365–371 (2007).
  Article CAS PubMed Google Scholar
• Erhardt, A., Biburger, M., Papadopoulos, T. & Tiegs, G. IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice. Hepatology 45, 475–485 (2007).
  Article CAS PubMed Google Scholar
• Ivars, F. T cell subset-specific expression of antigen receptor β chains in α chain-transgenic mice. Eur. J. Immunol. 22, 635–639 (1992).
  Article CAS PubMed Google Scholar
• Schumacher, A. et al. Mechanisms of action of regulatory T cells specific for paternal antigens during pregnancy. Obstet. Gynecol. 110, 1137–1145 (2007).
  Article CAS PubMed Google Scholar
• Mann, M. K., Maresz, K., Shriver, L. P., Tan, Y. & Dittel, B. N. B cell regulation of CD4+CD25+ T regulatory cells and IL-10 via B7 is essential for recovery from experimental autoimmune encephalomyelitis. J. Immunol. 178, 3447–3456 (2007).
  Article CAS PubMed Google Scholar
• Piccirillo, C. A. et al. CD4+CD25+ regulatory T cells can mediate suppressor function in the absence of transforming growth factor β1 production and responsiveness. J. Exp. Med. 196, 237–246 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Nakamura, K., Kitani, A. & Strober, W. Cell contact-dependent immunosuppression by CD4+CD25+ regulatory T cells is mediated by cell surface-bound transforming growth factor β. J. Exp. Med. 194, 629–644 (2001). This paper demonstrated that T Reg cells require cell-surface-bound TGFβ for their maximal regulatory activity.
  Article CAS PubMed PubMed Central Google Scholar
• Green, E. A., Gorelik, L., McGregor, C. M., Tran, E. H. & Flavell, R. A. CD4+CD25+ T regulatory cells control anti-islet CD8+ T cells through TGF-β–TGF-β receptor interactions in type 1 diabetes. Proc. Natl Acad. Sci. USA 100, 10878–10883 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Fahlen, L. et al. T cells that cannot respond to TGF-β escape control by CD4+CD25+ regulatory T cells. J. Exp. Med. 201, 737–746 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Li, M. O., Wan, Y. Y. & Flavell, R. A. T cell-produced transforming growth factor-b1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity 26, 579–591 (2007).
  Article CAS PubMed Google Scholar
• Strauss, L. et al. A unique subset of CD4+CD25highFoxp3+ T cells secreting interleukin-10 and transforming growth factor-β1 mediates suppression in the tumor microenvironment. Clin. Cancer Res. 13, 4345–4354 (2007).
  Article CAS PubMed Google Scholar
• Hilchey, S. P., De, A., Rimsza, L. M., Bankert, R. B. & Bernstein, S. H. Follicular lymphoma intratumoral CD4+CD25+GITR+ regulatory T cells potently suppress CD3/CD28-costimulated autologous and allogeneic CD8+. J. Immunol. 178, 4051–4061 (2007).
  Article CAS PubMed Google Scholar
• Li, H. et al. CD4+CD25+ regulatory T cells decreased the antitumor activity of cytokine-induced killer (CIK) cells of lung cancer patients. J. Clin. Immunol. 27, 317–326 (2007).
  Article CAS PubMed Google Scholar
• Clayton, A., Mitchell, J. P., Court, J., Mason, M. D. & Tabi, Z. Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2. Cancer Res. 67, 7458–7466 (2007).
  Article CAS PubMed Google Scholar
• Xia, Z. W. et al. Heme oxygenase-1 attenuates ovalbumin-induced airway inflammation by up-regulation of Foxp3 T-regulatory cells, interleukin-10, and membrane-bound transforming growth factor-β1. Am. J. Pathol. 171, 1904–1914 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Ostroukhova, M. et al. Treg-mediated immunosuppression involves activation of the Notch-HES1 axis by membrane-bound TGF-β. J. Clin. Invest. 116, 996–1004 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Collison, L. W. et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450, 566–569 (2007). This paper was the first to describe the inhibitory cytokine IL-35 and its requirement for maximal T Reg -cell maximal regulatory activity.
  Article CAS PubMed Google Scholar
• Gavin, M. A. et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445, 771–775 (2007).
  Article CAS PubMed Google Scholar
• Lieberman, J. The ABCs of granule-mediated cytotoxicity: new weapons in the arsenal. Nature Rev. Immunol. 3, 361–370 (2003).
  Article CAS Google Scholar
• Grossman, W. J. et al. Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells. Blood 104, 2840–2848 (2004).
  Article CAS PubMed Google Scholar
• McHugh, R. S. et al. CD4+CD25+ immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 16, 311–323 (2002).
  Article CAS PubMed Google Scholar
• Herman, A. E., Freeman, G. J., Mathis, D. & Benoist, C. CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J. Exp. Med. 199, 1479–1489 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Gondek, D. C., Lu, L. F., Quezada, S. A., Sakaguchi, S. & Noelle, R. J. Cutting edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J. Immunol. 174, 1783–1786 (2005). This paper was the first to demonstrate that T Reg cells have cytolytic capacity and regulate in a granzyme-B-dependent manner. Reference 66 subsequently showed that the granzyme-dependent lytic activity of T Reg cells was required for their regulatory activity in vivo.
  Article CAS PubMed Google Scholar
• Zhao, D. M., Thornton, A. M., DiPaolo, R. J. & Shevach, E. M. Activated CD4+CD25+ T cells selectively kill B lymphocytes. Blood 107, 3925–3932 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Cao, X. et al. Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity 27, 635–646 (2007).
  Article CAS PubMed Google Scholar
• Ren, X. et al. Involvement of cellular death in TRAIL/DR5-dependent suppression induced by CD4+CD25+ regulatory T cells. Cell Death. Differ. 14, 2076–2084 (2007).
  Article CAS PubMed Google Scholar
• Garin, M. I. et al. Galectin-1: a key effector of regulation meditated by CD4+CD25+ T cells. Blood 109, 2058–2065 (2007).
  Article CAS PubMed Google Scholar
• de la Rosa, M., Rutz, S., Dorninger, H. & Scheffold, A. Interleukin-2 is essential for CD4+CD25+ regulatory T cell function. Eur. J. Immunol. 34, 2480–2488 (2004).
  Article CAS PubMed Google Scholar
• Fontenot, J. D., Rasmussen, J. P., Gavin, M. A. & Rudensky, A. Y. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nature Immunol. 6, 1142–1151 (2005).
  Article CAS Google Scholar
• Duthoit, C. T., Mekala, D. J., Alli, R. S. & Geiger, T. L. Uncoupling of IL-2 signaling from cell cycle progression in naive CD4+ T cells by regulatory CD4+CD25+ T lymphocytes. J. Immunol. 174, 155–163 (2005).
  Article CAS PubMed Google Scholar
• Pandiyan, P., Zheng, L., Ishihara, S., Reed, J. & Lenardo, M. J. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nature Immunol. 8, 1353–1362 (2007).
  Article CAS Google Scholar
• Oberle, N., Eberhardt, N., Falk, C. S., Krammer, P. H. & Suri-Payer, E. Rapid suppression of cytokine transcription in human CD4+CD25− T cells by CD4+Foxp3+ regulatory T cells: independence of IL-2 consumption, TGF-β, and various inhibitors of TCR signaling. J. Immunol. 179, 3578–3587 (2007).
  Article CAS PubMed Google Scholar
• Deaglio, S. et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J. Exp. Med. 204, 1257–1265 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Borsellino, G. et al. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110, 1225–1232 (2007).
  Article CAS PubMed Google Scholar
• Kobie, J. J. et al. T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5′-adenosine monophosphate to adenosine. J. Immunol. 177, 6780–6786 (2006). References 74–76 collectively revealed the ability of T Reg cells to generate the inhibitory molecule adenosine by selective expression of CD39 and CD73. Reference 79 showed that another inhibitory adenosine nucleoside, cAMP, is directly transferred into effector T cells via gap junctions.
  Article CAS PubMed Google Scholar
• Zarek, P. E. et al. A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood 111, 251–259 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Oukka, M. Interplay between pathogenic Th17 and regulatory T cells. Ann. Rheum. Dis. 66 (Suppl 3), iii87–90 (2007).
  CAS PubMed PubMed Central Google Scholar
• Bopp, T. et al. Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J. Exp. Med. 204, 1303–1310 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Bluestone, J. A. & Tang, Q. How do CD4+CD25+ regulatory T cells control autoimmunity? Curr. Opin. Immunol. 17, 638–642 (2005).
  Article CAS PubMed Google Scholar
• Tang, Q. et al. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nature Immunol. 7, 83–92 (2006).
  Article CAS Google Scholar
• Tadokoro, C. E. et al. Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo. J. Exp. Med. 203, 505–511 (2006). References 81 and 82 revealed the importance of T Reg -cell–DC interactions as a mechanism for blocking effector-T-cell activation.
  Article CAS PubMed PubMed Central Google Scholar
• Read, S., Malmstrom, V. & Powrie, F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+ CD4+ regulatory cells that control intestinal inflammation. J. Exp. Med. 192, 295–302 (2000). This paper demonstrated that T Reg cells require CTLA4 for their maximal regulatory activity in vivo.
  Article CAS PubMed PubMed Central Google Scholar
• Oderup, C., Cederbom, L., Makowska, A., Cilio, C. M. & Ivars, F. Cytotoxic T lymphocyte antigen-4-dependent down-modulation of costimulatory molecules on dendritic cells in CD4+ CD25+ regulatory T-cell-mediated suppression. Immunology 118, 240–249 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Serra, P. et al. CD40 ligation releases immature dendritic cells from the control of regulatory CD4+CD25+ T cells. Immunity 19, 877–889 (2003).
  Article CAS PubMed Google Scholar
• Fallarino, F. et al. Modulation of tryptophan catabolism by regulatory T cells. Nature Immunol. 4, 1206–1212 (2003). This paper shows that T Reg cells initiate the IDO-mediated catabolism of tryptophan in a CTLA4-dependent manner.
  Article CAS Google Scholar
• Mellor, A. L. & Munn, D. H. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nature Rev. Immunol. 4, 762–774 (2004).
  Article CAS Google Scholar
• Cederbom, L., Hall, H. & Ivars, F. CD4+CD25+ regulatory T cells down-regulate co-stimulatory molecules on antigen-presenting cells. Eur. J. Immunol. 30, 1538–1543 (2000).
  Article CAS PubMed Google Scholar
• Kryczek, I. et al. Cutting edge: induction of B7-H4 on APCs through IL-10: novel suppressive mode for regulatory T cells. J. Immunol. 177, 40–44 (2006).
  Article CAS PubMed Google Scholar
• Lewkowich, I. P. et al. CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function. J. Exp. Med. 202, 1549–1561 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• 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. 176, 5293–5298 (2006).
  Article CAS PubMed Google Scholar
• Misra, N., Bayry, J., Lacroix-Desmazes, S., Kazatchkine, M. D. & Kaveri, S. V. Cutting edge: human CD4+CD25+ T cells restrain the maturation and antigen-presenting function of dendritic cells. J. Immunol. 172, 4676–4680 (2004).
  Article CAS PubMed Google Scholar
• Taams, L. S. et al. Modulation of monocyte/macrophage function by human CD4+CD25+ regulatory T cells. Hum. Immunol. 66, 222–230 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Tiemessen, M. M. et al. CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc. Natl Acad. Sci. USA 104, 19446–19451 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Workman, C. J. & Vignali, D. A. A. Negative regulation of T cell homeostasis by LAG-3 (CD223). J. Immunol. 174, 688–695 (2004).
  Article Google Scholar
• Huang, C. T. et al. Role of LAG-3 in regulatory T cells. Immunity 21, 503–513 (2004).
  Article CAS PubMed Google Scholar
• Liang, B. et al. Regulatory T cells inhibit dendritic cells by LAG-3 engagement of MHC class II. J. Immunol. 180, 5916–5926 (2008).
  Article CAS PubMed Google Scholar
• Baecher-Allan, C., Wolf, E. & Hafler, D. A. MHC class II expression identifies functionally distinct human regulatory T cells. J. Immunol. 176, 4622–4631 (2006).
  Article CAS PubMed Google Scholar
• Sarris, M., Andersen, K. G., Randow, F., Mayr, L. & Betz, A. G. Neuropilin-1 expression on regulatory T cells enhances their interactions with dendritic cells during antigen recognition. Immunity 28, 402–413 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Lu, L. F. et al. Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 442, 997–1002 (2006).
  Article CAS PubMed Google Scholar
• Kaplan, D. Autocrine secretion and the physiological concentration of cytokines. Immunol. Today 17, 303–304 (1996).
  Article CAS PubMed Google Scholar
• Kleinewietfeld, M. et al. CCR6 expression defines regulatory effector/memory-like cells within the CD25+CD4+ T-cell subset. Blood 105, 2877–2886 (2005).
  Article CAS PubMed Google Scholar
• Baecher-Allan, C., Wolf, E. & Hafler, D. A. MHC class II expression identifies functionally distinct human regulatory T cells. J. Immunol. 176, 4622–4631 (2006).
  Article CAS PubMed Google Scholar
• Thornton, A. M., Donovan, E. E., Piccirillo, C. A. & Shevach, E. M. Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function. J. Immunol. 172, 6519–6523 (2004).
  Article CAS PubMed Google Scholar
• Kim, J. M., Rasmussen, J. P. & Rudensky, A. Y. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nature Immunol. 8, 191–197 (2007).
  Article CAS Google Scholar
• Fontenot, J. D. et al. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22, 329–341 (2005).
  Article CAS PubMed Google Scholar
• Yi, H., Zhen, Y., Jiang, L., Zheng, J. & Zhao, Y. The phenotypic characterization of naturally occurring regulatory CD4+CD25+ T cells. Cell. Mol. Immunol. 3, 189–195 (2006).
  CAS PubMed Google Scholar
• Seddiki, N. et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J. Exp. Med. 203, 1693–1700 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Liu, W. et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ TReg cells. J. Exp. Med. 203, 1701–1711 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Yamaguchi, T. et al. Control of immune responses by antigen-specific regulatory T cells expressing the folate receptor. Immunity 27, 145–159 (2007).
  Article CAS PubMed Google Scholar
• Fontenot, J. D., Dooley, J. L., Farr, A. G. & Rudensky, A. Y. Developmental regulation of Foxp3 expression during ontogeny. J. Exp. Med. 202, 901–906 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Hsieh, C. S. et al. Recognition of the peripheral self by naturally arising CD25+CD4+ T cell receptors. Immunity 21, 267–277 (2004).
  Article CAS PubMed Google Scholar
• Izcue, A., Coombes, J. L. & Powrie, F. Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation. Immunol. Rev. 212, 256–271 (2006).
  Article CAS PubMed Google Scholar
• Roncarolo, M. G. et al. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol. Rev. 212, 28–50 (2006).
  Article CAS PubMed Google Scholar
• Chen, W. et al. Conversion of peripheral CD4+CD25−T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Mucida, D. et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–260 (2007).
  Article CAS PubMed Google Scholar
• Coombes, J. L. et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J. Exp. Med. 204, 1757–1764 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Sun, C. M. et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204, 1775–1785 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Benson, M. J., Pino-Lagos, K., Rosemblatt, M. & Noelle, R. J. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J. Exp. Med. 204, 1765–1774 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Schambach, F., Schupp, M., Lazar, M. A. & Reiner, S. L. Activation of retinoic acid receptor-α favours regulatory T cell induction at the expense of IL-17-secreting T helper cell differentiation. Eur. J. Immunol. 37, 2396–2399 (2007).
  Article CAS PubMed Google Scholar
• Kang, S. G., Lim, H. W., Andrisani, O. M., Broxmeyer, H. E. & Kim, C. H. Vitamin A metabolites induce gut-homing FoxP3+ regulatory T cells. J. Immunol. 179, 3724–3733 (2007).
  Article CAS PubMed Google Scholar
• Travis, M. A. et al. Loss of integrin αvβ8 on dendritic cells causes autoimmunity and colitis in mice. Nature 449, 361–365 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Matsumura, Y. et al. Selective expansion of Foxp3-positive regulatory T cells and immunosuppression by suppressors of cytokine signaling 3-deficient dendritic cells. J. Immunol. 179, 2170–2179 (2007).
  Article CAS PubMed Google Scholar
• Pyzik, M. & Piccirillo, C. A. TGF-β1 modulates Foxp3 expression and regulatory activity in distinct CD4+ T cell subsets. J. Leukoc. Biol. 82, 335–346 (2007).
  Article CAS PubMed Google Scholar
• Wei, J. et al. Antagonistic nature of T helper 1/2 developmental programs in opposing peripheral induction of Foxp3+ regulatory T cells. Proc. Natl Acad. Sci. USA 104, 18169–18174 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Grossman, W. J. et al. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21, 589–601 (2004).
  Article CAS PubMed Google Scholar
• Bluestone, J. A. & Abbas, A. K. Natural versus adaptive regulatory T cells. Nature Rev. Immunol. 3, 253–257 (2003).
  Article CAS Google Scholar
• Liu, V. C. et al. Tumor evasion of the immune system by converting CD4+CD25− T cells into CD4+CD25+ T regulatory cells: role of tumor-derived TGF-β. J. Immunol. 178, 2883–2892 (2007).
  Article CAS PubMed Google Scholar