Role of regulatory T cells in human diseases

The discovery of regulatory T lymphocytes (Treg) that are actively involved in maintaining immune tolerance has led to new insights into mechanisms of tolerance breakdown in human diseases, including those resulting from allergic, autoimmune, or infectious causes. Congenital deficiency of CD4+CD25+ Treg cells caused by loss-of-function mutations in the gene encoding Foxp3 triggers a syndrome of lymphoproliferation and myeloproliferation, autoimmunity, and allergic dysregulation, whereas deficient allergen-specific Treg cell responses have been associated with a number of allergic and autoimmune disorders. Tolerization to allergens and autoantigens is associated with augmentation of Treg cell numbers and suppressive function, suggesting the manipulation of Treg cell activity as a potential strategy for future therapeutic interventions in allergic and autoimmune diseases. The discovery of regulatory T lymphocytes (Treg) that are actively involved in maintaining immune tolerance has led to new insights into mechanisms of tolerance breakdown in human diseases, including those resulting from allergic, autoimmune, or infectious causes. Congenital deficiency of CD4+CD25+ Treg cells caused by loss-of-function mutations in the gene encoding Foxp3 triggers a syndrome of lymphoproliferation and myeloproliferation, autoimmunity, and allergic dysregulation, whereas deficient allergen-specific Treg cell responses have been associated with a number of allergic and autoimmune disorders. Tolerization to allergens and autoantigens is associated with augmentation of Treg cell numbers and suppressive function, suggesting the manipulation of Treg cell activity as a potential strategy for future therapeutic interventions in allergic and autoimmune diseases. Regulatory T (Treg) cells are subsets of T cells involved in the maintenance of peripheral self-tolerance by actively suppressing the activation and expansion of autoreactive T cells. Several types of Treg cells have been characterized, most prominently natural and inducible CD4+CD25+ Treg cells. The latter have been propelled to the forefront of immunologic investigation by virtue of the identification in human subjects and in mice of a syndrome of lymphoproliferation, autoimmunity, and allergic dysregulation resulting from the absence of CD4+CD25+ Treg cells because of deleterious mutations in the transcriptional regulator Foxp3. This review focuses on the role of CD4+CD25+ Treg cells in human disease, with a particular emphasis on insights gained from studying human subjects and rodent models with failure of CD4+CD25+ Treg cell development and function caused by Foxp3 deficiency. The consequences of CD4+CD25+ Treg cell deficiency or dysfunction in the development of human allergic and autoimmune diseases are examined. Compelling evidence indicates a key role for Treg cells in the maintenance of self-tolerance. These cells mediate dominant suppression of autoreactive T cells normally present in the periphery, as well as downregulating immune responses to foreign antigens.1Bluestone J.A. Abbas A.K. Natural versus adaptive regulatory T cells.Nat Rev Immunol. 2003; 3: 253-257Crossref PubMed Scopus (907) Google Scholar, 2Umetsu D.T. Akbari O. Dekruyff R.H. Regulatory T cells control the development of allergic disease and asthma.J Allergy Clin Immunol. 2003; 112: 480-488Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar Among the several subpopulations of Treg cells identified to date, the naturally arising CD4+CD25+ Treg cells have emerged as being particularly critical for the maintenance of immunologic tolerance.3Sakaguchi S. 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Control of regulatory T cell development by the transcription factor Foxp3.Science. 2003; 299: 1057-1061Crossref PubMed Scopus (3935) Google Scholar Consistent with their function in maintaining self-tolerance, depletion of CD4+CD25+ Treg cells precipitates autoimmunity against multiple tissues.9Sakaguchi S. Sakaguchi N. Asano M. Itoh M. Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.J Immunol. 1995; 155: 1151-1164Crossref PubMed Google Scholar CD4+CD25+ Treg cells are anergic and do not produce IL-2.10Shevach E.M. CD4+ CD25+ suppressor T cells: more questions than answers.Nat Rev Immunol. 2002; 2: 389-400Crossref PubMed Google Scholar When stimulated, they suppress the proliferation and cytokine production of conventional CD4+CD25− T cells, as well as that of CD8+ T cells and established TH1 and TH2 cells.11Thornton A.M. Shevach E.M. 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CD4+CD25+ T cells regulate virus-specific primary and memory CD8+ T cell responses.J Exp Med. 2003; 198: 889-901Crossref PubMed Scopus (345) Google Scholar CD4+CD25+ Treg cells produce TGF-β and IL-10, 2 cytokines endowed with immunosuppressive functions that play critical functions in Treg cell biology (discussed later in this review). Suppression by CD4+CD25+ Treg cells can proceed by means of several mechanisms that might be differentially used depending on the microenvironment and the immunopathology being suppressed.15von Boehmer H. Mechanisms of suppression by suppressor T cells.Nat Immunol. 2005; 6: 338-344Crossref PubMed Scopus (687) Google Scholar In vitro, the dominant immunosuppressive mechanism used by CD4+CD25+ Treg cells appears to be cell contact and CTLA-4 dependent but might proceed independently of IL-10 and TGF-β.15von Boehmer H. Mechanisms of suppression by suppressor T cells.Nat Immunol. 2005; 6: 338-344Crossref PubMed Scopus (687) Google Scholar In vitro–activated CD4+CD25+ Treg cells express granzyme A and display perforin-dependent cytotoxicity against autologous target cells, suggesting a function for direct killing in immunosuppression.16Grossman W.J. Verbsky J.W. Barchet W. Colonna M. Atkinson J.P. Ley T.J. Human T regulatory cells can use the perforin pathway to cause autologous target cell death.Immunity. 2004; 21: 589-601Abstract Full Text Full Text PDF PubMed Scopus (459) Google Scholar In contrast, suppression in several in vivo systems could be demonstrated not only to be CTLA-4 dependent but also IL-10 dependent, TGF-β dependent, or both.15von Boehmer H. Mechanisms of suppression by suppressor T cells.Nat Immunol. 2005; 6: 338-344Crossref PubMed Scopus (687) Google Scholar TGF-β might act by directly engaging TGF-β receptor type II on target effector cells and might also be important for peripheral homeostasis of CD4+CD25+ Treg cells, indicating a pleiotropic function of this cytokine in supporting immunosuppression by Treg cells.17Green 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-beta-TGF-beta receptor interactions in type 1 diabetes.Proc Natl Acad Sci U S A. 2003; 100: 10878-10883Crossref PubMed Scopus (278) Google Scholar, 18Chen M.L. Pittet M.J. Gorelik L. Flavell R.A. Weissleder R. von Boehmer H. et al.Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo.Proc Natl Acad Sci U S A. 2005; 102: 419-424Crossref PubMed Scopus (350) Google Scholar, 19Marie J.C. Letterio J.J. Gavin M. Rudensky A.Y. TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells.J Exp Med. 2005; 201: 1061-1067Crossref PubMed Scopus (535) Google Scholar Natural CD4+CD25+ Treg cells develop in the thymus. Neonatal thymectomy is associated with the development of autoimmunity secondary to CD4+CD25+ Treg cell deficiency.20Asano M. Toda M. Sakaguchi N. Sakaguchi S. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation.J Exp Med. 1996; 184: 387-396Crossref PubMed Google Scholar Mechanisms regulating CD4+CD25+ Treg cell development in the thymus remain unclear. One set of studies support a mechanism whereby CD4+CD25+ Treg cell development involves high-affinity interaction of their T-cell receptor (TCR) with peptide/MHC ligands, especially those presented by thymic epithelial cells, at levels of avidity approaching those associated with clonal deletion.21Jordan M.S. Riley M.P. von Boehmer H. Caton A.J. 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Origin of regulatory T cells with known specificity for antigen.Nat Immunol. 2002; 3: 756-763Crossref PubMed Scopus (0) Google Scholar An alternative model suggests that the development of CD4+CD25+ Treg cells is induced by mechanisms other than recognition of self-agonist peptides but that CD4+CD25+ Treg cells are more resistant to agonist-induced clonal deletion, leading to the selective survival of CD4+CD25+ Treg cells at high-avidity TCR peptide–MHC interactions.25van Santen H.M. Benoist C. Mathis D. Number of T reg cells that differentiate does not increase upon encounter of agonist ligand on thymic epithelial cells.J Exp Med. 2004; 200: 1221-1230Crossref PubMed Scopus (163) Google Scholar In the periphery the majority of natural Treg cells constitutively express high levels of CD25 (CD25high), but a significant minority express low levels of CD25 (CD25low).26Fontenot J.D. Rasmussen J.P. Williams L.M. Dooley J.L. Farr A.G. Rudensky A.Y. 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Regulatory T cell lineage specification by the forkhead transcription factor foxp3.Immunity. 2005; 22: 329-341Abstract Full Text Full Text PDF PubMed Scopus (1280) Google Scholar The maintenance of CD4+CD25+ Treg cells in the periphery is critically dependent on the action of 2 cytokines, IL-2 and TGF-β. Although CD4+CD25+ Treg cells do not produce IL-2, they are dependent on this cytokine for development in the thymus and for homeostasis and activation of suppressor function in the periphery (see discussion later in this review).28Malek T.R. Bayer A.L. Tolerance, not immunity, crucially depends on IL-2.Nat Rev Immunol. 2004; 4: 665-674Crossref PubMed Scopus (450) Google Scholar In studies on TGF-β–deficient mice, TGF-β was found to be necessary to maintain Foxp3 expression, regulatory function, and pool size of peripheral CD4+CD25+ Treg cells but was not required for development of CD4+CD25+ Treg cells in the thymus.19Marie J.C. Letterio J.J. Gavin M. Rudensky A.Y. TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells.J Exp Med. 2005; 201: 1061-1067Crossref PubMed Scopus (535) Google Scholar In addition to natural CD4+CD25+ Treg cells, another species of CD4+CD25+ Treg cells can be derived in vitro through treatment of peripheral CD4+CD25− T cells with anti-TCR and anti-CD28 antibodies in the presence of TGF-β.27Wan Y.Y. Flavell R.A. Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter.Proc Natl Acad Sci U S A. 2005; 102: 5126-5131Crossref PubMed Scopus (320) Google Scholar, 29Chen W. Jin W. Hardegen N. Lei K.J. Li L. Marinos N. et al.Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3.J Exp Med. 2003; 198: 1875-1886Crossref PubMed Scopus (2177) Google Scholar, 30Zheng S.G. Wang J.H. Gray J.D. Soucier H. Horwitz D.A. 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Marinos N. et al.Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3.J Exp Med. 2003; 198: 1875-1886Crossref PubMed Scopus (2177) Google Scholar Whereas the production of murine adaptive CD4+CD25+ Treg cells in vitro by cross-linking of the TCR and CD28 stimulation is absolutely dependent on TGF-β, it has been reported that human adaptive CD4+C25+ Treg cells can be induced in vitro in the absence of TGF-β, but this observation was not reproduced in independent studies.32Walker M.R. Kasprowicz D.J. Gersuk V.H. Benard A. Van Landeghen M. Buckner J.H. et al.Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25- T cells.J Clin Invest. 2003; 112: 1437-1443Crossref PubMed Google Scholar, 33Yagi H. Nomura T. Nakamura K. Yamazaki S. Kitawaki T. 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In vivo instruction of suppressor commitment in naive T cells.J Exp Med. 2004; 199: 1401-1408Crossref PubMed Scopus (472) Google Scholar demonstrated that CD4+CD25+ Foxp3+ Treg cells could be derived de novo from peripheral CD4+ naive T cells through continuous infusion of a submitogenic concentration of an agonistic peptide. The second approach used RAG-deficient mice repopulated with monoclonal T- and B-cell populations that are otherwise devoid of natural CD4+CD25+ Treg cells. Whereas intraperitoneal immunization of these mice is associated with the induction of hyper-IgE and lung inflammation, oral antigen administration is associated with tolerance induction mediated by oral antigen–induced CD4+CD25+ Foxp3+ Treg cells.35Mucida D. Kutchukhidze N. Erazo A. Russo M. Lafaille J.J. Curotto de Lafaille M.A. Oral tolerance in the absence of naturally occurring Tregs.J Clin Invest. 2005; 115: 1923-1933Crossref PubMed Scopus (203) Google Scholar These results from both in vitro and in vivo experimental systems reveal a surprising plasticity of the CD4+CD25− populations to develop de novo into CD4+CD25+ Treg cells, with obvious implications for the treatment of human diseases with ex vivo–derived Treg populations or with immunotherapy, as is already used in allergic diseases. A more general question relates to the temporal requirement for Foxp3 expression to maintain natural CD4+CD25+ Treg cell phenotype in the periphery. Transgenic expression of Foxp3 in the thymus fails to rescue the lethal phenotype of Foxp3-deficient mice, which is consistent with a requirement for Foxp3 expression in the periphery.36Khattri R. Kasprowicz D. Cox T. Mortrud M. Appleby M.W. Brunkow M.E. et al.The amount of scurfin protein determines peripheral T cell number and responsiveness.J Immunol. 2001; 167: 6312-6320PubMed Google Scholar However, whether Foxp3 function is continuously required to maintain CD4+CD25+ Treg cells in the periphery throughout the lifespan of the organism remains an open question. The identification of the forkhead-type factor Foxp3 as a master switch gene for CD4+CD25+ Treg cells has provided a pivotal breakthrough in our understanding of CD4+CD25+ Treg cell development and function. Foxp3 was originally identified as the gene product affected in a lethal X-linked recessive lymphoproliferative disease in mice and human subjects.37Godfrey V.L. Wilkinson J.E. Russell L.B. X-linked lymphoreticular disease in the scurfy (sf) mutant mouse.Am J Pathol. 1991; 138: 1379-1387PubMed Google Scholar Loss-of-function mutations in the gene encoding Foxp3 underlie the lymphoproliferative disease of the scurfy mouse. 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The latter has been implicated in studies on other Foxp subfamily members (Foxp1, Foxp2, and Foxp4) in the formation of Foxp homodimers and heterodimers.51Wang B. Lin D. Li C. Tucker P. Multiple domains define the expression and regulatory properties of Foxp1 forkhead transcriptional repressors.J Biol Chem. 2003; 278: 24259-24268Crossref PubMed Scopus (109) Google Scholar, 52Li S. Weidenfeld J. Morrisey E.E. Transcriptional and DNA binding activity of the Foxp1/2/4 family is modulated by heterotypic and homotypic protein interactions.Mol Cell Biol. 2004; 24: 809-822Crossref PubMed Scopus (125) Google Scholar A praline-rich N-terminal domain mediates transcriptional suppression (Chatila TA, unpublished observations, August 2005). Single amino acid deletions in the leucine zipper domain and missense and nonsense mutations and deletions in the forkhead homology domain have been associated with the development of IPEX in human subjects, which is consistent with a functionally critical role of the respective domain in Foxp3 function (Fig 2).43Chatila T.A. Blaeser F. Ho N. Lederman H.M. Voulgaropoulos C. Helms C. et al.JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome.J Clin Invest. 2000; 106: R75-R81Crossref PubMed Google Scholar A 2-bp insertion in exon 8 of Foxp3 leading to a translational frame shift and a premature stop codon underlines the genetic defect in the scurfy mouse.42Brunkow M.E. Jeffery E.W. Hjerrild K.A. Paeper B. Clark L.B. 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Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to repress cytokine gene expression and effector functions of T helper cells.Proc Natl Acad Sci U S A. 2005; 102: 5138-5143Crossref PubMed Scopus (304) Google Scholar Foxp3-mediated transcriptional suppression of key T-cell cytokine genes, including those encoding IL-2, IL-4, and IFN-γ, underlies the inability of CD4+CD25+ Treg cells to secrete these cytokines. The role of the respective domains in transcriptional regulation by Foxp3 remains elusive, as is the mechanism by which it interacts with and suppresses transcriptional activation. The immunopathology of Foxp3 deficiency results from unchecked T-cell activ