The Foxp3+ regulatory T cell: a jack of all trades, master of regulation (original) (raw)

• Gershon, R.K. & Kondo, K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology 18, 723–737 (1970).
  CAS PubMed PubMed Central Google Scholar
• Benacerraf, B., Kapp, J.A., Debre, P., Pierce, C.W. & de la Croix, F. The stimulation of specific suppressor T cells in genetic non-responder mice by linear random copolymers of L-amino acids. Transplant. Rev. 26, 21–38 (1975).
  CAS PubMed Google Scholar
• Bach, J.F., Boitard, C., Yasunami, R. & Dardenne, M. Control of diabetes in NOD mice by suppressor cells. J. Autoimmun. 3 Suppl 1, 97–100 (1990).
  PubMed 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).
  CAS PubMed Google Scholar
• Herbelin, A., Gombert, J.M., Lepault, F., Bach, J.F. & Chatenoud, L. Mature mainstream TCR αβ+CD4+ thymocytes expressing L-selectin mediate “active tolerance” in the nonobese diabetic mouse. J. Immunol. 161, 2620–2628 (1998).
  CAS PubMed Google Scholar
• Hall, B.M., Pearce, N.W., Gurley, K.E. & Dorsch, S.E. Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. III. Further characterization of the CD4+ suppressor cell and its mechanisms of action. J. Exp. Med. 171, 141–157 (1990).
  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).
  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. Nat. Immunol. 4, 330–336 (2003).
  CAS PubMed Google Scholar
• Khattri, R., Cox, T., Yasayko, S.A. & Ramsdell, F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat. Immunol. 4, 337–342 (2003).
  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).
  CAS PubMed Google Scholar
• Faria, A.M. & Weiner, H.L. Oral tolerance. Immunol. Rev. 206, 232–259 (2005).
  CAS PubMed Google Scholar
• Chang, C.C. et al. Tolerization of dendritic cells by TS cells: the crucial role of inhibitory receptors ILT3 and ILT4. Nat. Immunol. 3, 237–243 (2002).
  CAS PubMed Google Scholar
• Kronenberg, M. Toward an understanding of NKT cell biology: progress and paradoxes. Annu. Rev. Immunol. 23, 877–900 (2005).
  CAS PubMed Google Scholar
• Zhang, Z.X., Yang, L., Young, K.J., DuTemple, B. & Zhang, L. Identification of a previously unknown antigen-specific regulatory T cell and its mechanism of suppression. Nat. Med. 6, 782–789 (2000).
  CAS PubMed Google Scholar
• Hayday, A. & Tigelaar, R. Immunoregulation in the tissues by γδ T cells. Nat. Rev. Immunol. 3, 233–242 (2003).
  CAS PubMed Google Scholar
• Bluestone, J.A. & Abbas, A.K. Natural versus adaptive regulatory T cells. Nat. Rev. Immunol. 3, 253–257 (2003).
  CAS PubMed Google Scholar
• Malek, T.R., Yu, A., Vincek, V., Scibelli, P. & Kong, L. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rβ-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17, 167–178 (2002).
  CAS PubMed Google Scholar
• Kim, J.M., Rasmussen, J.P. & Rudensky, A.Y. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8, 191–197 (2007).
  CAS PubMed Google Scholar
• Gambineri, E., Torgerson, T.R. & Ochs, H.D. Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr. Opin. Rheumatol. 15, 430–435 (2003).
  CAS PubMed Google Scholar
• Sakaguchi, S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol. 22, 531–562 (2004).
  CAS PubMed Google Scholar
• Qin, S. et al. “Infectious” transplantation tolerance. Science 259, 974–977 (1993).
  CAS PubMed Google Scholar
• Tarbell, K.V. et al. Dendritic cell-expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice. J. Exp. Med. 204, 191–201 (2007).
  CAS PubMed PubMed Central Google Scholar
• Mempel, T.R. et al. Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity 25, 129–141 (2006).
  CAS PubMed Google Scholar
• Piccirillo, C.A. & Shevach, E.M. Cutting edge: control of CD8+ T cell activation by CD4+CD25+ immunoregulatory cells. J. Immunol. 167, 1137–1140 (2001).
  CAS PubMed 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).
  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).
  CAS PubMed 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).
  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).
  CAS PubMed PubMed Central Google Scholar
• Qin, H.Y. et al. A novel mechanism of regulatory T cell-mediated down-regulation of autoimmunity. Int. Immunol. 18, 1001–1015 (2006).
  CAS PubMed Google Scholar
• Tang, Q. et al. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat. Immunol. 7, 83–92 (2006).
  CAS PubMed Google Scholar
• Tang, Q. & Krummel, M.F. Imaging the function of regulatory T cells in vivo. Curr. Opin. Immunol. 18, 496–502 (2006).
  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. Nat. Immunol. 8, 1353–1362 (2007).
  CAS PubMed Google Scholar
• Valenzuela, H.F. et al. O-glycosylation regulates LNCaP prostate cancer cell susceptibility to apoptosis induced by galectin-1. Cancer Res. 67, 6155–6162 (2007).
  CAS PubMed Google Scholar
• Toscano, M.A. et al. Differential glycosylation of TH1, TH2 and TH-17 effector cells selectively regulates susceptibility to cell death. Nat. Immunol. 8, 825–834 (2007).
  CAS PubMed Google Scholar
• Jonuleit, H. et al. Infectious tolerance: human CD25+ regulatory T cells convey suppressor activity to conventional CD4+ T helper cells. J. Exp. Med. 196, 255–260 (2002).
  CAS PubMed PubMed Central Google Scholar
• Dieckmann, D., Bruett, C.H., Ploettner, H., Lutz, M.B. & Schuler, G. Human CD4+CD25+ regulatory, contact-dependent T cells induce interleukin 10-producing, contact-independent type 1-like regulatory T cells. J. Exp. Med. 196, 247–253 (2002).
  CAS PubMed PubMed Central 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).
  CAS PubMed PubMed Central Google Scholar
• Munn, D.H. & Mellor, A.L. IDO and tolerance to tumors. Trends Mol. Med. 10, 15–18 (2004).
  CAS PubMed Google Scholar
• Mellor, A.L. & Munn, D. Policing pregnancy: Tregs help keep the peace. Trends Immunol. 25, 563–565 (2004).
  CAS PubMed Google Scholar
• Puccetti, P. & Grohmann, U. IDO and regulatory T cells: a role for reverse signalling and non-canonical NF-κB activation. Nat. Rev. Immunol. 7, 817–823 (2007).
  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).
  CAS PubMed PubMed Central Google Scholar
• Tang, Q. et al. Distinct roles of CTLA-4 and TGF-β in CD4+CD25+ regulatory T cell function. Eur. J. Immunol. 34, 2996–3005 (2004).
  CAS PubMed Google Scholar
• Read, S. et al. Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo. J. Immunol. 177, 4376–4383 (2006).
  CAS PubMed Google Scholar
• Chikuma, S. & Bluestone, J.A. Expression of CTLA-4 and FOXP3 in cis protects from lethal lymphoproliferative disease. Eur. J. Immunol. 37, 1285–1289 (2007).
  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).
  CAS PubMed PubMed Central Google Scholar
• Pesu, M., Muul, L., Kanno, Y. & O'Shea, J.J. Proprotein convertase furin is preferentially expressed in T helper 1 cells and regulates interferon γ. Blood 108, 983–985 (2006).
  CAS PubMed PubMed Central 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).
  CAS PubMed PubMed Central 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).
  CAS PubMed 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).
  CAS PubMed PubMed Central Google Scholar
• You, S., Thieblemont, N., Alyanakian, M.A., Bach, J.F. & Chatenoud, L. Transforming growth factor-β and T-cell-mediated immunoregulation in the control of autoimmune diabetes. Immunol. Rev. 212, 185–202 (2006).
  CAS PubMed Google Scholar
• Belkaid, Y., Piccirillo, C.A., Mendez, S., Shevach, E.M. & Sacks, D.L. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420, 502–507 (2002).
  CAS PubMed Google Scholar
• Maloy, K.J. et al. CD4+CD25+ TR cells suppress innate immune pathology through cytokine-dependent mechanisms. J. Exp. Med. 197, 111–119 (2003).
  CAS PubMed PubMed Central Google Scholar
• Li, M.O., Wan, Y.Y. & Flavell, R.A. T cell-produced transforming growth factor-β1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity 26, 579–591 (2007).
  CAS PubMed Google Scholar
• Wilson, M.S. et al. Suppression of allergic airway inflammation by helminth-induced regulatory T cells. J. Exp. Med. 202, 1199–1212 (2005).
  CAS PubMed PubMed Central Google Scholar
• Kullberg, M.C. et al. TGF-β1 production by CD4+ CD25+ regulatory T cells is not essential for suppression of intestinal inflammation. Eur. J. Immunol. 35, 2886–2895 (2005).
  CAS PubMed Google Scholar
• Choi, B.M., Pae, H.O., Jeong, Y.R., Kim, Y.M. & Chung, H.T. Critical role of heme oxygenase-1 in Foxp3-mediated immune suppression. Biochem. Biophys. Res. Commun. 327, 1066–1071 (2005).
  CAS PubMed Google Scholar
• Xia, Z.W. et al. Heme oxygenase-1-mediated CD4+CD25high regulatory T cells suppress allergic airway inflammation. J. Immunol. 177, 5936–5945 (2006).
  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).
  CAS PubMed PubMed Central Google Scholar
• Kubach, J. et al. Human CD4+CD25+ regulatory T cells: proteome analysis identifies galectin-10 as a novel marker essential for their anergy and suppressive function. Blood 110, 1550–1558 (2007).
  CAS PubMed Google Scholar
• Garin, M.I. et al. Galectin-1: a key effector of regulation mediated by CD4+CD25+ T cells. Blood 109, 2058–2065 (2007).
  CAS PubMed Google Scholar
• Terness, P. et al. Tolerance signaling molecules and pregnancy: IDO, galectins, and the renaissance of regulatory T cells. Am. J. Reprod. Immunol. 58, 238–254 (2007).
  CAS PubMed Google Scholar
• Collison, L.W. et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450, 566–569 (2007).
  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).
  CAS PubMed Google Scholar
• Belkaid, Y., Blank, R.B. & Suffia, I. Natural regulatory T cells and parasites: a common quest for host homeostasis. Immunol. Rev. 212, 287–300 (2006).
  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).
  CAS PubMed 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).
  CAS PubMed Google Scholar
• Jordan, M.S. et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat. Immunol. 2, 301–306 (2001).
  CAS PubMed Google Scholar
• Waterhouse, P. et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270, 985–988 (1995).
  CAS PubMed Google Scholar
• Shull, M.M. et al. Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992).
  CAS PubMed PubMed Central Google Scholar
• Pasare, C. & Medzhitov, R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299, 1033–1036 (2003).
  CAS PubMed Google Scholar
• Balasa, B., Van Gunst, K., Jung, N., Katz, J.D. & Sarvetnick, N. IL-10 deficiency does not inhibit insulitis and accelerates cyclophosphamide-induced diabetes in the nonobese diabetic mouse. Cell. Immunol. 202, 97–102 (2000).
  CAS PubMed Google Scholar
• Suri-Payer, E. & Cantor, H. Differential cytokine requirements for regulation of autoimmune gastritis and colitis by CD4+CD25+ T cells. J. Autoimmun. 16, 115–123 (2001).
  CAS PubMed Google Scholar
• Hara, M. et al. IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo. J. Immunol. 166, 3789–3796 (2001).
  CAS PubMed 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).
  CAS PubMed PubMed Central Google Scholar
• Belghith, M. et al. TGF-β-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes. Nat. Med. 9, 1202–1208 (2003).
  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).
  CAS PubMed PubMed Central Google Scholar
• Takahashi, T. et al. Immunologic self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 192, 303–310 (2000).
  CAS PubMed PubMed Central Google Scholar
• Salomon, B. & Bluestone, J.A. Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu. Rev. Immunol. 19, 225–252 (2001).
  CAS PubMed Google Scholar
• Kingsley, C.I., Karim, M., Bushell, A.R. & Wood, K.J. CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponses. J. Immunol. 168, 1080–1086 (2002).
  CAS PubMed 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).
  CAS PubMed Google Scholar
• Sawitzki, B. et al. IFN-γ production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo. J. Exp. Med. 201, 1925–1935 (2005).
  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).
  CAS PubMed Google Scholar
• Zelenay, S., Chora, A., Soares, M.P. & Demengeot, J. Heme oxygenase-1 is not required for mouse regulatory T cell development and function. Int. Immunol. 19, 11–18 (2007).
  CAS PubMed Google Scholar
• Sato, K. et al. Carbon monoxide generated by heme oxygenase-1 suppresses the rejection of mouse-to-rat cardiac transplants. J. Immunol. 166, 4185–4194 (2001).
  CAS PubMed Google Scholar