Transforming growth factor-β-induced regulatory T cells referee inflammatory and autoimmune diseases
© BioMed Central Ltd 2005
Published: 24 January 2005
Naturally occurring CD4+CD25+ regulatory T cells mediate immune suppression to limit immunopathogenesis associated with chronic inflammation, persistent infections and autoimmune diseases. Their mode of suppression is contact-dependent, antigen-nonspecific and involves a nonredundant contribution from the cytokine transforming growth factor (TGF)-β. Not only can TGF-β mediate cell–cell suppression between the regulatory T cells and CD4+CD25- or CD8+ T cells, but new evidence also reveals its role in the conversion of CD4+CD25- T cells, together with TCR antigen stimulation, into the regulatory phenotype. Elemental to this conversion process is induction of expression of the forkhead transcription factor, Foxp3. This context-dependent coercion of naive CD4+ T cells into a powerful subset of regulatory cells provides a window into potential manipulation of these cells to orchestrate therapeutic intervention in diseases characterized by inadequate suppression, as well as a promising means of controlling pathologic situations in which excessive suppression dominates.
Autoimmune diseases are characterized by a loss of regulation of T cell growth and activation, with resultant overexuberant inflammation and tissue destruction. Although T cell responses to foreign antigens are essential to our protection from a plethora of potentially pathogenic agents and microbes, T cell responses to self antigens can be overtly deleterious. As the signaling pathways associated with T cell activation continue to be illuminated, there is also an emerging excitement about naturally occurring opposing forces that can exert control over antigen-activated T cells to prevent reactivity to self. Suppressor T cells, implicated in this regulatory process decades ago, fell into ill repute but have recently re-emerged not only as a real population but as a population crucial to immune homeostasis, maintenance of tolerance, and prevention of the onset of autoimmune disease. Their existence is no longer in question, but true to their history these cells, their origin, generation, and mechanisms of action have generated considerable controversy. Recognition of the potential impact of these cells in clinical cellular therapy has driven a rapid expansion of the field in order to understand and manipulate the regulatory T cell population to devise strategies to control autoimmunity, transplantation tolerance, tumor immunity, allergy and infectious diseases, particularly HIV.
The essentiality of this endogenous population in protecting the host from disproportionate T cell activation and autoreactive effector cells is underscored both in experimental models and in humans in which the numbers and/or function of Treg are compromised [6, 10, 16–20]. In mice, depletion of CD4+CD25+ T cells by neonatal (day 3) thymectomy leads to spontaneous development of organ-specific autoimmune diseases, including autoimmune thyroiditis, gastritis, and wasting , which can be reversed by adoptive transfer of Treg . Treg are pivotal in the protection of lymphopenic mice from induced inflammatory bowel disease, experimental autoimmune encephalomyelitis, diabetes, and allergy [16, 18, 22]. In infectious models, Treg also influence the effector immune response, as is evident in Leishmania major infection .
Both innate and adaptive immune responses are subject to Treg control. Triggering of dendritic cells by Toll-like receptor ligands expressed by invading pathogens leads to the production of soluble factors, including IL-6, that may render effector cells refractory to regulatory activity . Moreover, activated dendritic cells produce TGF-β, which may further influence the development of Treg . By such intersecting pathways, the innate and regulatory arms of the immune system have the capacity to exert sufficient control over each other to enable effector cells to mount efficient immune responses with minimal pathology. In human infectious, neoplastic, and autoimmune diseases, Treg activities often mirror those in murine systems. Numbers of Treg are reportedly reduced in human autoimmune diseases [17, 25], although their significance in the evolution of immunopathogenesis remains an area of continued exploration. Moreover, increased CD4+CD25+ regulatory T cells have been reported in HIV-1 immunodeficiency , and in lung cancer patients the increased numbers of CD4+CD25+ regulatory T cells directly inhibit autologous T cell proliferation . Thus, this unique and persuasive population of regulatory T cells has a crucial role in the maintenance of tolerance and immune homeostasis through immune suppression.
Mechanism of Treg suppression
Treg are both anergic, at least in vitro, and immunosuppressive. The absence of Treg results in the breakdown of tolerance and the development of autoimmune diseases . Our understanding of the functional domain of these cells has rapidly advanced through cell culture experiments. In vitro, the ability of CD4+CD25+ Treg to suppress responder T cell proliferation and cytokine production requires their activation, is dependent on cell contact, and is antigen nonspecific [1, 6, 10]. After years of searching for the elusive mediator(s) of suppression consistent with the accepted cell-contact-dependent mechanism, membrane-associated TGF-β was identified as a pivotal perpetrator [6, 7, 14]. In this regard, latent TGF-β was first reported to be constitutively present on the surface of Treg [6, 7]; subsequently, active TGF-β was identified [6, 8, 14]. In vitro stimulation with anti-CD3 and antigen-presenting cells (APCs) enhances membrane-bound active TGF-β, which is consistent with the requirement that Treg activation promotes their suppressive potential [6, 13] (W Chen, unpublished data). Blockade of cell-surface TGF-β with neutralizing antibodies, with soluble TGF-β receptor, or with recombinant latency-associated peptide disrupts the ability of these cells to block responder T cell proliferation, confirming TGF-β as an instrument of suppression [6–8, 12, 13, 15, 29]. Still missing was the connecting link by which membrane-bound TGF-β could interact with the CD4+CD25- responder cells. Recently, TGF-β receptor type II (TβRII) was detected at elevated levels on responder T cells once they were activated through their TCR, thereby providing the molecular bridge by which TGF-β on the Treg orchestrates suppression of the responder cells [6, 8, 12].
TGF-β signaling and regulation
TGF-β is a potent cytokine and growth factor whose biological activity is primarily regulated post-translationally , because it is transcribed and translated as a small latent complex composed not only of active TGF-β, but also of a latency-associated peptide (LAP) to which it is noncovalently bound and which prevents its interaction with its specific receptors on the target cell surface. This small latent complex can be associated with the latent TGF-β1-binding protein, forming a large latent complex thought to serve as a tether for binding proteins and matrix molecules . In this configuration, TGF-β is not active but requires cleavage or dissociation from LAP to enable its interaction with its cognate receptor complex, TβRII and TβRI . Activation of TGF-β can occur by any of a number of mechanisms including cleavage with plasmin , interaction with αvβ6 , or through an ill-defined interaction of LAP with thrombospondin I (TSP-I), a ligand for the CD36 receptor . Adding credence to a role for TSP-1, the TSP-1-null mice exhibit persistent inflammation, particularly in the pancreas and lung, and display a phenotype with similarities to TGF-β-null mice [36, 37], although to a lesser extent because alternative mechanisms of TGF-β activation compensate. Nonetheless, TSP-1 is a major activator of TGF-β1 in vivo , and a TSP peptide that activates TGF-β reverses the TSP-1-null phenotype by dampening the tissue inflammation. In a feedback loop, TGF-β augments TSP secretion by dendritic cells and macrophages, and TGF-β-treated APCs facilitate the generation of regulatory T cells , creating an environment favorable for the induction of suppression and/or tolerance to ensure the blunting of any inflammatory reaction.
Often seeming paradoxical, activated TGF-β has both stimulatory and inhibitory influences on T cell function [6, 8]. These apparently disparate effects are dependent on context, including state of differentiation, presence of other growth factors or cytokines, matrix molecules, additional proximal cell populations, and membrane receptor levels. Beyond its involvement in contact-dependent suppression, soluble TGF-β can directly inhibit T cell proliferation, suppress macrophage activation and modulate dendritic cell function in its role as an immunoregulatory cytokine. Deletion of this cytokine is associated with lethal immune dysregulation and multi-organ inflammatory disease [39, 40].
In mediating its suppressive effects, TGF-β signals through the type I and type II TGF-β serine–threonine kinase receptors, TβRI and TβRII. Interaction of the TGF-β ligand with these receptors on target cells engages a signaling cascade precipitated by the phosphorylation of cytosolic proteins identified as Smads [41, 42]. When CD4+CD25+ Treg are co-cultured with TCR-activated CD4+CD25- responder T cells, there is a rapid engagement of this intracellular signaling pathway that is consistent with TGF-β as the link between these two cells and the impending functional inhibition manifested in the responder cell population [6, 12, 15]. In this regard, phosphorylation of Smads, initially detected with antibodies that recognize both Smad2 and Smad3  (W Chen, unpublished data), and more recently with Smad2-specific antibodies , occurred within minutes after exposure of responder T cells to Treg. Smad2 and Smad3 serve as receptor-activated Smad signaling intermediates, whereas Smad4 is a common Smad that complexes with Smad2/3 to enable translocation to the nucleus. Once within the nucleus, the Smad complex may interact with specific DNA sequences and with multiple specific transcription factors, in addition to transcriptional coactivators and/or co-repressors, culminating in the transcription of target genes and the transduction of a variety of signals dependent on the target cell . Smad2/3 are anchored to the plasma membrane through the Smad anchor for receptor activation (SARA), which probably increases the efficiency of activation by the TGF-β-receptor complexes . Smad2, rather than Smad3, may be the critical connector in the intracellular signaling pathway engaged in the responder cells by Treg surface-bound TGF-β, because mice deficient in Smad3 respond to Treg suppression and also to exogenous TGF-β  (W Chen, unpublished data). In addition to that mediated by Smad2, TGF-β signaling is regulated by complex mechanisms in the cytoplasm and nucleus. Beyond engaging Smad activity, TGF-β triggers the extracellular signal-related kinase and p38 mitogen-activated kinase pathways  to link additional signaling cascades involved in modulating cell function.
Perturbations in this immunoregulatory circuit can occur through dysregulation of the inhibitory Smad, Smad7, which typically represses TGF-β signaling by interacting with activated TGF-β receptors to prevent the activation of Smad2/3 and/or by interfering with complex formation between Smad2/3 and Smad4 . Facilitating the inhibitory Smad signals are the Smad ubiquitin regulatory factors (Smurfs), E3 ubiquitin ligases, capable of inducing polyubiquitination and degradation of TβRI [46, 47]. Smad7 is inducible by TGF-β itself as part of a feedback loop, as well as by the IFN-γ and NF-κB pathways . Moreover, the transcriptional co-repressors c-Ski and SnoN, by means of their interactions with Smad2/3/4, repress TGF-β-induced transcription and are upregulated by TGF-β as another negative feedback loop to maintain control of this incredibly powerful molecule . Dissection of these circuits will probably reveal pathways by which suppression can be manipulated to orchestrate changes in aberrant immunity.
Although the preponderance of evidence supports a major role for TGF-β in the mediation of Treg suppressive activity, there are likely to be additional factors and/or cofactors that secondarily contribute to their function and that may become prevalent in the absence of TGF-β and/or if TGF-β is dysregulated. The identification and intersection points of such pathways await further study. Among the factors that contribute to the regulation of TGF-β in CD4+CD25+ Treg are CD28, cytotoxic T lymphocyte antigen-4, glucocorticoid-induced TNF receptor and forkhead/winged helix or forkhead box P3 encoded by Foxp3 [48–51].
Generation of Treg
Although Treg were originally considered to derive only from thymic precursors , to be exported to the periphery, and to represent less than 10% of CD4+ T cells , thereby limiting their potential for manipulation for therapeutic considerations, important new evidence documents that Treg can be expanded and/or induced de novo from CD4+CD25- precursor T cells. How, where, and if the size and function of this population can be intentionally controlled is of the utmost importance. The thymic derivation of Treg is genetically as well as developmentally regulated, but it seems to be constitutive and relatively stable. Recruitment to a site of autoimmune reactivity may increase their numbers locally, but in a limited fashion. The ability to coerce expansion of functional Treg opens up possibilities for the manipulation of inflammation and immunity. CD4+CD25+ Treg undergo proliferation with TCR stimulation in the presence of high doses of exogenous IL-2 (more than 100 U/ml) in vitro . Importantly, these expanded CD4+CD25+ regulatory T cells preserve their anergic features and immunosuppressive ability once IL-2 is removed. This unique aspect of CD4+CD25+ Treg has definite potential application in designing future clinical therapy for autoimmune diseases, inflammation and transplantation. Nonetheless, the insufficiency of naturally derived CD4+CD25+ Treg in autoimmunity and other immune diseases has driven the search for approaches to convert normal naive CD4+CD25-T cells into CD4+CD25+ regulatory T cells.
The generation of functionally uncompromised CD4+CD25+ Treg involves the unique induction of forkhead/winged helix transcription factor Foxp3 (Scurfin) in Foxp3-negative CD4+CD25- precursors. Foxp3 is highly conserved, and in both mice and humans genetically defective Foxp3 is associated with autoimmune and inflammatory disease [48, 53–57]. In Foxp3 null mice, the deficiency of CD4+CD25+ Treg results in a lethal autoimmune syndrome [53, 55, 57]. In vitro, gene transfer of Foxp3 converts naive CD4+CD25- T cells into phenotypic and functional Treg [48, 53, 55, 56], which is consistent with the ability to rescue Foxp3-null mice with adoptive transfer of Treg . These data support the pivotal and nonredundant role of this transcription factor in Treg development and function. Conversely, the overexpression of Foxp3 in a transgenic mouse model results in enhanced numbers of CD4+CD25+ Treg and, furthermore, Foxp3-expressing CD4+CD25-, as well as CD4-CD8+, T cells in these transgenic mice constitutively exhibit suppressive functions .
Despite the success of the artificial gene transfer of Foxp3 into CD4+CD25- naive T cells to coerce them into a CD4+CD25+ regulatory T cell phenotype, the existence of a physiologic inducer of Foxp3 was unknown. The recent elucidation of a signaling pathway leading to the conversion of CD4+CD25- precursors into Treg revealed a pivotal role for TGF-β [8, 12, 14]. Moreover, the genetic deletion of Foxp3 results in an overlapping phenotype with the TGF-β1-null mice , implicating a connection and/or shared mechanism of action. The induction of gene expression of Foxp3, a transcription factor unique to Treg [48, 53–57] is, in fact, TGF-β dependent . However, TGF-β cannot act independently on precursor cells to generate Treg but requires co-stimulation through TCR and IL-2R [12, 58]. Naive splenic CD4+CD25- T cells cultured for 7 to 9 days with TCR stimulation and TGF-β in the presence of APCs emerge as CD4+CD25+ Treg with the ability to suppress CD4+ responder T cell proliferation. A similar conversion pattern occurs in TCR transgenic mice if the CD4+CD25- naive T cells are stimulated with specific antigen and APCs with TGF-β added . This engagement of the TCR and co-stimulator molecules (such as CD28) [49, 50, 59, 60] in concert with TβRII ligation triggers signaling pathways that culminate in Foxp3 transcription, which is essential to generation of Treg. In this fashion, TGF-β is not only expressed by Treg but also programs their development and function.
TGF-β-converted Treg control immune responses in vivo
Treg in autoimmune diseases
Human systemic lupus erythematosus (SLE) patients and murine models of SLE manifest a wide range of immunological abnormalities. The most pervasive of these include the generation of pathogenic autoantibodies. In this regard, 98% of human SLE patients possess antinuclear antibodies and 50 to 80% of these have anti-double-stranded DNA antibodies, the result of unchecked B lymphocyte activation and antibody production, probably due to uncontrolled T cell hyper-responsiveness. Both Th1 and Th2 responses are elevated, as demonstrated by the upregulation of proinflammatory cytokines, notably IFN-γ, IL-6, IL-12, and IL-10, as well as T cell-dependent autoantibody production. Interestingly, these T and B lymphocyte abnormalities have been attributed, at least partly, to defective production and function of TGF-β [12, 66]. In contrast to strong suspicions, few data yet exist as to whether the uncontrolled T and B cell activation and pathogenesis in SLE can be attributed to a deficiency in CD4+CD25+ regulatory T cells. In this regard, one study indicated that CD4+CD25+ T cells were significantly decreased in patients with active SLE in comparison with normal subjects and patients with an inactive stage of the disease , and in another recent study  Treg were reported to be abnormal in number, phenotype, and function in patients with active SLE. However, the exact role of the decreased CD4+CD25+ Treg levels in the pathogenesis of SLE awaits demonstration of a significant correlation between the levels of CD4+CD25+ Treg and inactive disease or flare activity .
In rheumatoid arthritis (RA), the relationship between CD4+CD25+ Treg and Th1-dependent pathogenesis of the disease also remains under study. It was recently suggested  that no significant difference in suppressive activity was found between CD4+CD25+ T cells from peripheral blood of RA patients and healthy control subjects, although the numbers may be less . Nonetheless, CD4+CD25+ T cells from synovial fluid reportedly had a significantly higher suppressive activity than those in peripheral blood of RA patients. Notably, despite the presence of these highly functional Treg in synovial fluid, there was still ongoing inflammation in the joints, indicating the complex picture of RA pathogenesis, which might reflect a prominent imbalance between regulatory and inflammatory checkpoints. In an encouraging experimental therapy study, patients with RA who were treated for 6 months with oral dnaJP1, a peptide that induces proinflammatory T cell responses in naive RA patients, manifested increased Foxp3+CD4+CD25+ T cells, suggesting that the treatment induced the emergence (enhancement) of T cells with the regulatory phenotype . In short, despite the complex picture of Treg in autoimmunity, it can be envisioned that it will become feasible to manipulate regulatory T cells for therapeutic benefit. With continued efforts, a better understanding and more advanced techniques will emerge for the induction and/or expansion of Treg to enhance their role in autoimmunity, allergy, and graft rejection.
Innate and adaptive immune responses are essential to protect the host from a plethora of potentially pathogenic microorganisms, but countermeasures to prevent reactivity of self are equally essential. Although protection against self-recognition-induced autoimmunity is accomplished in large part by the central deletion of autoreactive T cells during intrathymic development, this process is not perfect and self-reactive escapees can wreak havoc on the immune system. However, among the backup pathways in the periphery to protect us from self-destruction are deletion, anergy, ignorance, and active suppression. Among these, current interest has zeroed in on CD4+CD25+ regulatory T cells, which can profoundly suppress responder T cell proliferation and cytokines in vitro and in vivo. Originally considered an exclusive product of the thymus, important new data indicate that these cells can be generated from peripheral CD4+ T cells and expanded for delivery as a cellular therapeutic strategy. Opportunities to use suppressor T cell populations in the treatment of debilitating autoimmune diseases, allergy, chronic infectious diseases, and transplant rejection are no longer a dream of the future but are an emerging reality. Moreover, as we illuminate the mechanisms of regulation of these Treg, it might also become feasible to diminish, rather than augment, their numbers/activity to promote tumor rejection and vaccine responses and/or to reverse immunodeficiency diseases.
systemic lupus erythematosus
transforming growth factor
T helper cell
regulatory T cell(s)
- Sakaguchi S: Regulatory T cells: key controllers of immunologic self-tolerance. Cell. 2000, 101: 455-458. 10.1016/S0092-8674(00)80856-9.View ArticlePubMed
- Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH: Identification and functional characterization of human CD4+CD25+ T cells with regulatory properties isolated from peripheral blood. J Exp Med. 2001, 193: 1285-1294. 10.1084/jem.193.11.1285.PubMed CentralView ArticlePubMed
- Levings MK, Sangregorio R, Roncarolo MG: Human CD25+CD4+ T regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function. J Exp Med. 2001, 193: 1295-1302. 10.1084/jem.193.11.1295.PubMed CentralView ArticlePubMed
- 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. 2001, 193: 1303-1310. 10.1084/jem.193.11.1303.PubMed CentralView ArticlePubMed
- Taams LS, Smith J, Rustin MH, Salmon M, Poulter LW, Akbar AN: Human anergic/suppressive CD4+CD25+ T cells: a highly differentiated and apoptosis-prone population. Eur J Immunol. 2001, 31: 1122-1131. 10.1002/1521-4141(200104)31:4<1122::AID-IMMU1122>3.0.CO;2-P.View ArticlePubMed
- Chen W, Wahl SM: TGF-β: the missing link in CD4+CD25+ regulatory T cell-mediated immunosuppression. Cytokine Growth Factor Rev. 2003, 14: 85-89. 10.1016/S1359-6101(03)00003-0.View ArticlePubMed
- 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 beta. J Exp Med. 2001, 194: 629-644. 10.1084/jem.194.5.629.PubMed CentralView ArticlePubMed
- Wahl SM, Chen W: TGF-β: how tolerant can it be?. Immunol Res. 2003, 28: 167-179. 10.1385/IR:28:3:167.View ArticlePubMed
- Oida T, Zhang X, Goto M, Hachimura S, Totsuka M, Kaminogawa S, Weiner HL: CD4+CD25- T cells that express latency-associated peptide on the surface suppress CD4+CD45RBhigh-induced colitis by a TGF-beta-dependent mechanism. J Immunol. 2003, 170: 2516-2522.View ArticlePubMed
- Shevach EM: CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol. 2002, 2: 389-400.PubMed
- Piccirillo CA, Letterio JJ, Thornton AM, McHugh RS, Mamura M, Mizuhara H, Shevach EM: CD4+CD25+ regulatory T cells can mediate suppressor function in the absence of transforming growth factor beta1 production and responsiveness. J Exp Med. 2002, 196: 237-246. 10.1084/jem.20020590.PubMed CentralView ArticlePubMed
- Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM: 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: 1875-1886. 10.1084/jem.20030152.PubMed CentralView ArticlePubMed
- Annunziato F, Cosmi L, Liotta F, Lazzeri E, Manetti R, Vanini V, Romagnani P, Maggi E, Romagnani S: Phenotype, localization, and mechanism of suppression of CD4+CD25+ human thymocytes. J Exp Med. 2002, 196: 379-387. 10.1084/jem.20020110.PubMed CentralView ArticlePubMed
- Wahl SM, Swisher J, McCartney-Francis N, Chen W: TGF-beta: the perpetrator of immune suppression by regulatory T cells and suicidal T cells. J Leukoc Biol. 2004, 76: 15-24. 10.1189/jlb.1103539.View ArticlePubMed
- Nakamura K, Kitani A, Fuss I, Pedersen A, Harada N, Nawata H, Strober W: TGF-beta1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J Immunol. 2004, 172: 834-842.View ArticlePubMed
- Annacker O, Pimenta-Araujo R, Burlen-Defranoux O, Bandeira A: On the ontogeny and physiology of regulatory T cells. Immunol Rev. 2001, 182: 5-17. 10.1034/j.1600-065X.2001.1820101.x.View ArticlePubMed
- Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA: Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med. 2004, 199: 971-979. 10.1084/jem.20031579.PubMed CentralView ArticlePubMed
- Furtado GC, Olivares-Villagomez D, Curotto de Lafaille MA, Wensky AK, Latkowski JA, Lafaille JJ: Regulatory T cells in spontaneous autoimmune encephalomyelitis. Immunol Rev. 2001, 182: 122-134. 10.1034/j.1600-065X.2001.1820110.x.View ArticlePubMed
- Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M, Kuniyasu Y, Nomura T, Toda M, Takahashi T: Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev. 2001, 182: 18-32. 10.1034/j.1600-065X.2001.1820102.x.View ArticlePubMed
- Belkaid Y, Piccirillo CA, Mendez S, Shevach EM, Sacks DL: CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature. 2002, 420: 502-507. 10.1038/nature01152.View ArticlePubMed
- Asano 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: 387-396. 10.1084/jem.184.2.387.View ArticlePubMed
- Shevach EM, McHugh RS, Piccirillo CA, Thornton AM: Control of T-cell activation by CD4+ CD25+ suppressor T cells. Immunol Rev. 2001, 182: 58-67. 10.1034/j.1600-065X.2001.1820104.x.View ArticlePubMed
- Pasare C, Medzhitov R: Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science. 2003, 299: 1033-1036. 10.1126/science.1078231.View ArticlePubMed
- Verhasselt V, Vosters O, Beuneu C, Nicaise C, Stordeur P, Goldman M: Induction of FOXP3-expressing regulatory CD4pos T cells by human mature autologous dendritic cells. Eur J Immunol. 2004, 34: 762-772. 10.1002/eji.200324552.View ArticlePubMed
- Bluestone JA, Abbas AK: Natural versus adaptive regulatory T cells. Nat Rev Immunol. 2003, 3: 253-257. 10.1038/nri1032.View ArticlePubMed
- Kinter AL, Hennessey M, Bell A, Kern S, Lin Y, Daucher M, Planta M, McGlaughlin M, Jackson R, Ziegler SF, Fauci AS: CD25(+)CD4(+) regulatory T cells from the peripheral blood of asymptomatic HIV-infected individuals regulate CD4(+) and CD8(+) HIV-specific T cell immune responses in vitro and are associated with favorable clinical markers of disease status. J Exp Med. 2004, 200: 331-343. 10.1084/jem.20032069.PubMed CentralView ArticlePubMed
- Woo EY, Yeh H, Chu CS, Schlienger K, Carroll RG, Riley JL, Kaiser LR, June CH: Cutting edge: regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol. 2002, 168: 4272-4276.View ArticlePubMed
- Sakaguchi 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: 1151-1164.PubMed
- Zhang X, Izikson L, Liu L, Weiner HL: Activation of CD25+CD4+ regulatory T cells by oral antigen administration. J Immunol. 2001, 167: 4245-4253.View ArticlePubMed
- Khalil N: TGF-beta: from latent to active. Microbes Infect. 1999, 1: 1255-1263. 10.1016/S1286-4579(99)00259-2.View ArticlePubMed
- Oklu R, Hesketh R: The latent transforming growth factor β binding protein (LTBP) family. Biochem J. 2000, 352: 601-610. 10.1042/0264-6021:3520601.PubMed CentralView ArticlePubMed
- Shi Y, Massagué J: Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell. 2003, 113: 685-700. 10.1016/S0092-8674(03)00432-X.View ArticlePubMed
- Annes JP, Munger JS, Rifkin DB: Making sense of latent TGFβ activation. J Cell Sci. 2003, 116: 217-224. 10.1242/jcs.00229.View ArticlePubMed
- Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J, Pittet JF, Kaminski N, Garat C, Matthay MA, et al: The integrin αvβ6 binds and activates latent TGFβ1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell. 1999, 96: 319-328. 10.1016/S0092-8674(00)80545-0.View ArticlePubMed
- Murphy-Ullrich JE, Poczatek M: Activation of latent TGF-beta by thrombospondin-1: mechanisms and physiology. Cytokine Growth Factor Rev. 2000, 11: 59-69. 10.1016/S1359-6101(99)00029-5.View ArticlePubMed
- Crawford SE, Stellmach V, Murphy-Ullrich JE, Ribeiro SM, Lawler J, Hynes RO, Boivin GP, Bouck N: Thrombospondin-1 is a major activator of TGF-β1 in vivo. Cell. 1998, 93: 1159-1170. 10.1016/S0092-8674(00)81460-9.View ArticlePubMed
- Lawler J, Sunday M, Thibert V, Duquette M, George EL, Rayburn H, Hynes RO: Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia. J Clin Invest. 1998, 101: 982-992.PubMed CentralView ArticlePubMed
- Masli S, Turpie B, Hecker KH, Streilein JW: Expression of thrombospondin in TGFbeta-treated APCs and its relevance to their immune deviation-promoting properties. J Immunol. 2002, 168: 2264-2273.View ArticlePubMed
- Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, Roberts AB, Sporn MB, Ward JM, Karlsson S: Transforming growth factor β1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA. 1993, 90: 770-774.PubMed CentralView ArticlePubMed
- Christ M, McCartney-Francis NL, Kulkarni AB, Ward JM, Mizel DE, Mackall CL, Gress RE, Hines KL, Tian H, Karlsson S, et al: Immune dysregulation in TGF-beta 1-deficient mice. J Immunol. 1994, 153: 1936-1946.PubMed
- Miyazono K, ten Dijke P, Heldin CH: TGF-beta signaling by Smad proteins. Adv Immunol. 2000, 75: 115-157.View ArticlePubMed
- Roberts AB: TGF-beta signaling from receptors to the nucleus. Microbes Infect. 1999, 1: 1265-1273. 10.1016/S1286-4579(99)00258-0.View ArticlePubMed
- Tsukazaki T, Chiang TA, Davison AF, Attisano L, Wrana JL: SARA, a FYVE domain protein that recruits Smad2 to the TGFβ receptor. Cell. 1998, 95: 779-791. 10.1016/S0092-8674(00)81701-8.View ArticlePubMed
- Takekawa M, Tatebayashi K, Itoh F, Adachi M, Imai K, Saito H: Smad-dependent GADD45β expression mediates delayed activation of p38 MAP kinase by TGF-β. EMBO J. 2002, 21: 6473-6482. 10.1093/emboj/cdf643.PubMed CentralView ArticlePubMed
- Suzuki C, Murakami G, Fukuchi M, Shimanuki T, Shikauchi Y, Imamura T, Miyazono K: Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane. J Biol Chem. 2002, 277: 39919-39925. 10.1074/jbc.M201901200.View ArticlePubMed
- Ebisawa T, Fukuchi M, Murakami G, Chiba T, Tanaka K, Imamura T, Miyazono K: Smurf1 interacts with transforming growth factor-β type I receptor through Smad7 and induces receptor degradation. J Biol Chem. 2001, 276: 12477-12480. 10.1074/jbc.C100008200.View ArticlePubMed
- Kavsak P, Rasmussen RK, Causing CG, Bonni S, Zhu H, Thomsen GH, Wrana JL: Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGFβ receptor for degradation. Mol Cell. 2000, 6: 1365-1375. 10.1016/S1097-2765(00)00134-9.View ArticlePubMed
- Schubert LA, Jeffery E, Zhang Y, Ramsdell F, Ziegler SF: Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J Biol Chem. 2001, 276: 37672-37679. 10.1074/jbc.M104521200.View ArticlePubMed
- Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, Bluestone JA: B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity. 2000, 12: 431-440. 10.1016/S1074-7613(00)80195-8.View ArticlePubMed
- Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S: Immunologic self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med. 2000, 192: 303-310. 10.1084/jem.192.2.303.PubMed CentralView ArticlePubMed
- 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. 2000, 192: 295-302. 10.1084/jem.192.2.295.PubMed CentralView ArticlePubMed
- Apostolou I, Sarukhan A, Klein L, von Boehmer H: Origin of regulatory T cells with known specificity for antigen. Nat Immunol. 2002, 3: 756-763.PubMed
- Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, Wilkinson JE, Galas D, Ziegler SF, Ramsdell F: Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet. 2001, 27: 68-73. 10.1038/83784.View ArticlePubMed
- Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, Buist N, Levy-Lahad E, Mazzella M, Goulet O, Perroni L, et al: X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. 2001, 27: 18-20. 10.1038/83707.View ArticlePubMed
- Fontenot JD, Gavin MA, Rudensky AY: Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003, 4: 330-336. 10.1038/ni904.View ArticlePubMed
- Hori S, Nomura T, Sakaguchi S: Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003, 299: 1057-1061. 10.1126/science.1079490.View ArticlePubMed
- Khattri R, Cox T, Yasayko SA, Ramsdell F: An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol. 2003, 4: 337-342. 10.1038/ni909.View ArticlePubMed
- Horwitz DA, Zheng SG, Gray JD: The role of the combination of IL-2 and TGF-beta or IL-10 in the generation and function of CD4+ CD25+ and CD8+ regulatory T cell subsets. J Leukoc Biol. 2003, 74: 471-478. 10.1189/jlb.0503228.View ArticlePubMed
- Liu Z, Geboes K, Hellings P, Maerten P, Heremans H, Vandenberghe P, Boon L, van Kooten P, Rutgeerts P, Ceuppens JL: B7 interactions with CD28 and CTLA-4 control tolerance or induction of mucosal inflammation in chronic experimental colitis. J Immunol. 2001, 167: 1830-1838.View ArticlePubMed
- Takahashi T, Kuniyasu Y, Toda M, Sakaguchi N, Itoh M, Iwata M, Shimizu J, Sakaguchi S: 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. 1998, 10: 1969-1980. 10.1093/intimm/10.12.1969.View ArticlePubMed
- Maloy KJ, Salaun L, Cahill R, Dougan G, Saunders NJ, Powrie F: CD4+CD25+ TR cells suppress innate immune pathology through cytokine-dependent mechanisms. J Exp Med. 2003, 197: 111-119. 10.1084/jem.20021345.PubMed CentralView ArticlePubMed
- Grundstrom S, Cederbom L, Sundstedt A, Scheipers P, Ivars F: Superantigen-induced regulatory T cells display different suppressive functions in the presence or absence of natural CD4+CD25+ regulatory T cells in vivo. J Immunol. 2003, 170: 5008-5017.View ArticlePubMed
- Montagnoli C, Bacci A, Bozza S, Gaziano R, Mosci P, Sharpe AH, Romani L: B7/CD28-dependent CD4+CD25+ regulatory T cells are essential components of the memory-protective immunity to Candida albicans. J Immunol. 2002, 169: 6298-6308.View ArticlePubMed
- Walker LS, Chodos A, Eggena M, Dooms H, Abbas AK: Antigen-dependent proliferation of CD4+ CD25+ regulatory T cells in vivo. J Exp Med. 2003, 198: 249-258. 10.1084/jem.20030315.PubMed CentralView ArticlePubMed
- Klein L, Khazaie K, von Boehmer H: In vivo dynamics of antigen-specific regulatory T cells not predicted from behavior in vitro. Proc Natl Acad Sci USA. 2003, 100: 8886-8891. 10.1073/pnas.1533365100.PubMed CentralView ArticlePubMed
- Chen W, Wahl SM: TGF-beta: receptors, signaling pathways and autoimmunity. Curr Dir Autoimmun. 2002, 5: 62-91.View ArticlePubMed
- Crispin JC, Martinez A, Alcocer-Varela J: Quantification of regulatory T cells in patients with systemic lupus erythematosus. J Autoimmun. 2003, 21: 273-276. 10.1016/S0896-8411(03)00121-5.View ArticlePubMed
- Valencia X, Olson D, He LS, Illei G, Lipsky P: CD4+CD25+ T regulatory cells in autoimmune diseases. Arthritis Rheum. 2003, 48 (Suppl. S): 411-
- Liu MF, Wang CR, Fung LL, Wu CR: Decreased CD4+CD25+ T cells in peripheral blood of patients with systemic lupus erythematosus. Scand J Immunol. 2004, 59: 198-202. 10.1111/j.0300-9475.2004.01370.x.View ArticlePubMed
- van Amelsfort J, Jacobs K, Bijlsma JWJ, Taams L, Lafeber F: CD4+CD25+ regulatory T cells in rheumatoid arthritis: differences in presence, phenotype and function between peripheral blood and synovial fluid. Arthritis Rheum. 2003, 48 (Suppl. S): 1159-
- Prakken BJ, Samodal R, Le TD, Giannoni F, Yung GP, Scavulli J, Amox D, Roord S, de Kleer I, Bonnin D, et al: Epitope-specific immunotherapy induces immune deviation of proinflammatory T cells in rheumatoid arthritis. Proc Natl Acad Sci USA. 2004, 101: 4228-4233. 10.1073/pnas.0400061101.PubMed CentralView ArticlePubMed