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Originally published online as doi:10.1189/jlb.1103539 on February 13, 2004

Published online before print February 13, 2004
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(Journal of Leukocyte Biology. 2004;76:15-24.)
© 2004 by Society for Leukocyte Biology

TGF-ß: the perpetrator of immune suppression by regulatory T cells and suicidal T cells

Sharon M. Wahl1, Jennifer Swisher, Nancy McCartney-Francis and Wanjun Chen

Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland

1Correspondence: OIIB, NIDCR, NIH, Building 30, Rm. 320, 30 Convent Drive, MSC4352, Bethesda, MD 20892-4352. E-mail: smwahl{at}dir.nidcr.nih.gov


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ABSTRACT
 
Innate and adaptive immunity function to eliminate foreign invaders and respond to injury while enabling coexistence with commensal microbes and tolerance against self and innocuous agents. Although most often effective in accomplishing these objectives, immunologic processes are not fail-safe and may underserve or be excessive in protecting the host. Checks and balances to maintain control of the immune system are in place and are becoming increasingly appreciated as targets for manipulating immunopathologic responses. One of the most recognized mediators of immune regulation is the cytokine transforming growth factor-ß (TGF-ß), a product of immune and nonimmune cells. Emerging data have unveiled a pivotal role for TGF-ß as a perpetrator of suppression by CD4+CD25+ regulatory T (Treg) cells and in apoptotic sequelae. Through its immunosuppressive prowess, TGF-ß effectively orchestrates resolution of inflammation and control of autoaggressive immune reactions by managing T cell anergy, defining unique populations of Treg cells, regulating T cell death, and influencing the host response to infections.

Key Words: immunoregulation • apoptosis • leishmania


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INTRODUCTION
 
The genesis of inflammation or pathogenesis of chronic inflammatory diseases, whether initiated by trauma, pathogens, or antigens, depends on the trafficking of inflammatory cells to the site of induction, their local activation, and release of mediators to recruit and activate additional populations. The precise molecular and microenvironmental mechanisms dictating this cellular infiltration and local retention continue to be deciphered, but equally compelling is the definition of the cells and mediators involved in the suppression of inflammation for the ultimate restoration of immune homeostasis. It is striking that one of the mediators orchestrating the genesis of inflammation is, paradoxically, also pivotal in the resolution of the response. How transforming growth factor-ß (TGF-ß) drives and serves as a brake for inflammation and immune responses remains enigmatic, but emerging studies paint a unique portrait of this immunoregulatory molecule.

As a secreted cytokine/growth factor, TGF-ß regulates multiple fundamental cellular processes including growth, migration, adhesion, extracellular matrix formation, and apoptosis. As initially reported more than a decade ago, TGF-ß is a potent chemotactic factor, recruiting monocytes, neutrophils, and lymphocytes at femtomolar concentrations [1 2 3 ], which provided the first evidence of its potential involvement in immune and inflammatory processes. Rapidly released by platelets at a site of injury or infection or by activated inflammatory cells themselves, TGF-ß not only influences recruitment but also adhesion and activation of circulating leukocytes [4 5 6 ], engaging an immunologic cascade for sequestration of the foreign agent, debridement, and tissue repair, essential to restoration of tissue integrity. Secreted as a latent molecule, TGF-ß is activated from its latent complex by proteolytic and nonproteolytic mechanisms [7 , 8 ] to bind to and trigger its cognate receptors on target cells. Once activated, TGF-ß elicits its cellular effects, including leukocyte chemotaxis, in a dose-dependent manner through cell-surface TGF-ß serine/threonine type I and II (TßRI and TßRII) receptors and engagement of a Smad (transcription factor activated by TGF-ß)-dependent signal [9 ]. Ligation of constitutively phosphorylated TßRII enlists and phosphorylates TßRI, initiating signal transduction powered through a novel family of Smad proteins. The activated TßRII–TßRI complex phosphorylates Smad2 and/or -3, which dissociate from the receptor complex and partner with Smad4 in a heteromeric complex that translocates into the nucleus as a transcription factor for TGF-ß-responsive genes [10 ]. Although Smad2 deletion is embryologically lethal [11 ], the Smad3 null mice exhibit a phenotype, which in some ways parallels the TGF-ß knockout mice [12 ]. Smad3 null mice develop inflammation, particularly in mucosal tissues, and chronic infections, in part, as a result of the defective chemotaxis of Smad3 null leukocytes toward TGF-ß [9 , 12 ]. However, as not all TGF-ß signaling occurs via Smad3, the null mice live longer with less-severe organ inflammation than the TGF-ß1 null mice [13 14 15 ].

As a counterbalance to the potent consequences of the TGF-ß signal-transduction scenario, there exist intracellular Smad proteins with inhibitory activity. Smad6 and -7 participate in negative-feedback loops that may regulate the intensity or duration of TGF-ß responses by binding to TßRI and disengaging activation of other Smads [16 , 17 ]. Smad7 expression is rapidly elevated in response to interferon-{gamma} (IFN-{gamma}) but also TGF-ß, resulting in down-regulated Smad2/3 activation and blunting of the TGF-ß signal [18 ]. As components of a more complex network, Smad proteins also intersect with nuclear factor-{kappa}B and mitogen-activated protein kinase (MAPK) signaling pathways [19 , 20 ] to mediate downstream TGF-ß regulatory circuits [21 ].

With the initial barrage of inflammatory mediators, including TGF-ß, at a site of injury/infection, a chain reaction is set in motion, with recruitment, proliferation, and activation of the cellular participants. Release of TGF-ß by leukocytes and local cell populations, in turn, induces newly emigrated, immature cells to generate additional cytokines including tumor necrosis factor {alpha} (TNF-{alpha}), interleukin (IL)-lß, and chemokines to perpetuate the response. This powerful promotion of inflammation is dependent not only on TGF-ß receptor capacity but also on the state of cellular differentiation and the micromilieu. It is important that resting cells are often turned on/activated when the TGF-ß ligand connects with its receptor, whereas once activated, inflammatory cells typically become susceptible to inhibition by TGF-ß, reflecting the ability of TGF-ß to operate as a switch factor, dependent on context [22 ]. Consistent with its complex and even apparent opposing effects in immunity, local expression or injection of TGF-ß generally favors its proinflammatory profile, and neutralization of this excess protein may ameliorate chronic inflammatory destructive and/or fibrotic pathogenesis [23 24 25 26 ].

Although cognizant of the dramatic role of TGF-ß in the onset and evolution of an immune/inflammatory response, this review will focus on the expanding appreciation for TGF-ß as a crucial agent in dimming the immune response and averting the harmful pathogenesis associated with unresolved inflammation. As TGF-ß molecules are highly conserved, it is likely that this cytokine represents an evolutionary adaptation designed to protect the host from overexuberant and tissue-destructive, inflammatory events. Clearly, in its ability to limit inflammation and modify innate and adaptive immunity, TGF-ß has no equal.


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TGF-ß AS AN INHIBITOR OF INFLAMMATION AND IMMUNITY
 
Based on our understanding that TGF-ß can suppress effector T cell [T helper cell type 1 (Th1) and Th2] and activated macrophage functions [6 , 27 ] and that most experimental autoimmune diseases are initiated and mediated by T cells, particularly Th1 cells, and are effected by phagocytic cells [6 ], a resurgence of enthusiasm for TGF-ß has occurred. Administration of exogenous TGF-ß protein systemically by gene transfer or by manipulation of T cells with TGF-ß before transfer, can prevent or inhibit experimental autoimmune diseases (reviewed in refs. [6 , 28 ]). As evident in vitro, the effects of in vivo TGF-ß administration on the development of autoimmune pathology depend on multiple parameters, including concentration, route, and time of delivery, presence of other cytokines, and the activation status of cellular targets. Although exogenous protein and/or gene transfer of TGF-ß may have potential in the treatment of chronic inflammatory and autoimmune diseases, these approaches are not without liability as a result of the ubiquitous presence of TGF-ß receptors. Consequently, the search continues for potential strategies to manipulate endogenous TGF-ß and control the genesis of immune disorders. One of the earliest, appreciated approaches to manipulation of immunopathogenesis through TGF-ß involves the induction of oral tolerance.


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ORAL TOLERANCE
 
The gastrointestinal tract, continually confronted with self and nonself antigens in its lumen, must rely on tolerizing mechanisms to prevent constant engagement of the mucosal immune system. Recognizing this evolutionary adaptation, investigators attempted to mimic the response by oral delivery of low-dose antigens and documented subsequent hyporesponsiveness to the ingested proteins [29 ]. The suppression of specific antigen as well as bystander antigen responses occurs by multiple mechanisms, but the generation of a population of Th3 cells [30 ] appears paramount. Among the molecules and strategies used by these cells to orchestrate immune suppression and tolerance is TGF-ß [30 31 32 33 34 ]. The efficacy of oral tolerance is linked to the dose and kinetics of antigen delivery in that low-dose antigen-feeding favors generation of regulatory T (Treg) cells, which mainly produce TGF-ß but also IL-4 and IL-10, whereas high-dose antigen drives anergy and/or apoptosis of antigen-specific Th1 as well as Th2 cells but not necessarily TGF-ß-producing Th3 cells [30 , 32 ]. From an interventional standpoint, oral administration of auto-antigens or nonself antigens can prevent and/or suppress experimental models of autoimmunity, chronic inflammation, and also transplantation rejection [29 , 32 ]. In orally tolerized animals, peripheral lymphoid tissues express increased levels of TGF-ß, which is reflected by elevated, circulating TGF-ß and a corresponding decrease in serum TNF-{alpha} and reduced clinical severity of disease [32 ]. Despite the success of inducing oral tolerance in animal models, clinical trials evaluating the impact of orally induced tolerance in humans have been less-clearly beneficial, likely reflecting the differences between inbred mice and complex disease processes in man [29 , 31 ] and warranting continued investigation.


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T CELL TARGETS OF TGF-ß SUPPRESSION
 
Whether TGF-ß is augmented endogenously via induction of oral tolerance or other routes of inducement or is administered exogenously, its ability to regulate the functional repertoire of T cells may be quite diverse depending on the local environs and whether the T cells are naïve, differentiated, or activated. The heterogeneity in response may reflect, in part, the level of expression of TGF-ß receptors, which are up-regulated when T cells are activated [35 , 36 ]. Moreover, TGF-ß itself increases receptor levels, implicating a feedback loop favoring suppression [23 ]. The critical nature of the TGF-ß–TßRII signaling pathway in regulating T cell function has been documented in transgenic mice in which expression of a dominant-negative TßRII under a T cell-specific promoter or overexpression of a dominant-negative TßRII on T cells culminates in spontaneous T cell activation and Th1 and Th2 cytokine release [37 , 38 ]. These transgenic mice may develop autoimmune, inflammatory disease, characterized by cellular invasion of several organs such as lung, colon, stomach, pancreas, and/or kidney. Although the receptor-defective mice do not display symptoms until 3–4 months of age, distinct from the phenotype of TGF-ß1 null mice, their immunologic, functional repertoire is clearly compromised. In humans, patients with Sezary syndrome, whose CD4+ T cells exhibit decreased surface TßRII, also have reduced responsiveness to the growth-inhibitory effects of TGF-ß1 and consequently, uncontrolled T cell proliferation [39 ].

The cytokine milieu is another factor underlying T cell vulnerability to the impact of TGF-ß, as exemplified by the ability of IL-2 to significantly perturb the inhibitory influence of TGF-ß [6 ]. IL-2 supports T cell proliferation [40 ], and TGF-ß, by inhibiting T-bet (Th1) or GATA3 (Th2) transcription factor expression [38 , 41 ], suppresses proliferation and cytokine responses. In a microenvironment replete with IL-2, typical of the initial phase of inflammation, early viral infection, or acute transplant rejection, when antigen-specific T cells are undergoing priming or activation, TGF-ß may foster their growth and differentiation [42 , 43 ]. In contrast, should IL-2 be selectively depleted, as may occur in a tumor site, virus-induced immunodeficiency, or in autoimmune disease remission, antigen-specific T cell responses are likely blunted by a micromilieu rich in active TGF-ß. Suppression of proliferation results not only from diminished IL-2 but likely also via TGF-ß suppression of c-Myc and enhancement of cell-cycle inhibitors, p15INK4b and p21CIP1 [44 ]. Likewise, a reciprocal relationship exists between IFN-{gamma} and TGF-ß, which involves IFN-{gamma} enhancement of inhibitory Smad7 expression to block TGF-ß signaling [45 , 46 ]. In turn, TGF-ß may directly inhibit IFN-{gamma} as well as IL-2 production by T cells or indirectly target IFN-{gamma} by suppressing CD40 expression and/or IL-12 production in antigen-presenting cells (APC) [46 , 47 ]. TGF-ß also counters the ability of macrophage or dendritic cell (DC)-derived IL-12 to activate T cell Janus tyrosine kinase–signal transducer and activator of transcription signaling pathways [48 , 49 ]. Confirming this opposing activity between IFN-{gamma} and TGF-ß, there is a profound augmentation of IFN-{gamma} and its downstream impact, particularly on macrophages, in mice lacking TGF-ß [50 ], which is pivotal in controlling macrophage-inducible nitric oxide synthase (iNOS), inducible cyclooxygenase, and matrix metalloproteinases, all of which become incendiary in its absence. These and related complex immunoregulatory circuits may influence induction of Treg cells and maintenance of immune suppression.


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Treg CELLS
 
Beyond Th3 cells implicated in oral tolerance, additional populations of T cells exhibit immunoregulatory and tolerogenic functions, including T regulatory type 1 (Tr1) and CD4+ T cells constitutively expressing IL-2 receptor {alpha} (IL-2R{alpha}) chain (CD4+CD25+ Treg) [51 , 52 ]. Two of these populations, Th3 and Tr1, manage their immunosuppressive actions mainly through the release of soluble factors, including TGF-ß and/or IL-10 [31 , 53 ]. Moreover, these cells do not function independently but rather network to mediate suppression. For example, Treg may govern the fate and distribution of Th3 and Tr1, according to their complement of adhesion receptors. {alpha}4ß7+ Treg might preferentially home to mucosal sites and convert CD4+ T cells into IL-10-producing Tr1-like cells, whereas {alpha}4ß1+ Treg, targeted to inflamed tissues (vascular cell adhesion molecule+), might drive development of TGF-ß-producing Th3-like cells, passing on the role of suppressors in a process of "infectious tolerance" [54 ] (Fig. 1 ).



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  		Figure 1. Generation and regulation of Treg cells. CD4+ T cells, triggered by antigen and APC, progress to Th1 (IFN-{gamma}) and/or Th2 (IL-4) mediators of immunity. CD4+CD25+ Treg cells are generated in the thymus or converted from CD4+CD25– responder T cells to generate TGF-ß and mediate suppression of CD4+CD25– responder T cell proliferation and cytokine production. Suppression involves cell contact between TGF-ß+TßRII+ Treg and activated responder cells, which become TßRII+. Treg may also orchestrate Th3 and/or Tr1 activity in target tissues. CD4+ responder cells may be released from Treg suppression when APC, triggered through Toll-like receptors (TLR), produce IL-6 and an unknown factor(s) (Factor X). The balance between activation (green arrow) and suppression (red arrow) underlies development of immunity and its resolution.

This unusual population of Treg mediates suppression via a distinct cell contact-dependent mechanism involving cell membrane-bound TGF-ß, cytotoxic T lymphocyte antigen (CTLA)-4, and glucocorticoid-induced TNFR (GITR) [36 , 52 53 54 55 ]. As regulators, Treg cells suppress induction and activity of Th1 and Th2 lymphocytes, promote tolerance, and diminish antitumor defense. Initial studies uncovering this potent CD4+ immunoregulatory T cell population capable of preventing autoaggressive behavior defined them by their expression of CD25, origination from the thymus, and small numbers (~10% of CD4+ T cells) [51 ]. Depletion of Treg before transfer of CD4+ T cells into immunocompromised mice resulted in a high incidence of organ-specific, autoimmune disease [51 ]. More recently, Treg cells have been shown to express a unique profile of markers including CTLA-4 [56 57 58 ] and GITR [59 , 60 ], both of which enable regulation of the regulators [34 , 61 ] (Fig. 1) . Not only are these Treg themselves anergic to T cell receptor (TCR) stimulation, but they markedly suppress proliferation of CD4+CD25– antigen-responsive T cells, in large part by blocking production of IL-2 [52 ] and in vitro, Treg-mediated suppression can be overcome by addition of IL-2 and anti-CD28 [36 , 52 ]. Treg cells need TCR engagement for optimal suppressive competence, but once stimulated, they suppress T cell activation in an antigen-nonspecific manner [52 ]. The recognized importance of Treg has propelled rapid and intense investigations to delineate the molecules and signal pathways that orchestrate their recruitment, activation, and function in anticipation of potential therapeutic insight.

In defining the molecular mechanisms underlying cell-contact dependency, at least in vitro, this population was recently shown to express cell-surface TGF-ß in its active and/or latent form [36 , 62 63 64 ] and TßRII [36 ], whereas CD4+CD25– T cells (responder cells) are virtually negative for membrane TGF-ß or TßRII, at least until after TCR activation [34 , 36 ]. Coexpression of active TGF-ß and TßRII on Treg may account not only for their own anergic state but also the functional interaction between their membrane-displayed TGF-ß and the inducible TßRII, which appear on responder CD4+ and CD8+ T cells following TCR activation, a pivotal maneuver underlying cell contact-dependent suppression [36 ] (Fig. 1) , although this mechanism is not uniformly accepted [65 ]. The indispensability of TßRII ligation on responder cells was convincingly documented in antigen-reactive CD8+ T cells bearing a dominant-negative TßRII, which were incapable of being suppressed by Treg [63 ].

As anticipated, cells with such potent regulatory activity must have their own set of regulators. Treg constitutively express CTLA-4 [56 57 58 ], and ligation of CTLA-4 induces production of TGF-ß [66 67 68 ] to enhance their suppressive prowess. Conforming to this role of CTLA-4 as a promoter of suppression, anti-CTLA-4 injection blocks Treg suppression of murine colitis [56 ]. In contrast to CTLA-4-augmented Treg function, GITR represents a counterbalance, and signaling through GITR blunts or reverses suppression [59 , 60 ], although the functional mechanism remains elusive. Our own studies indicate that GITR stimulation in Treg may interfere with the TGF-ß signaling cascade (W. Chen et al., unpublished). In addition to IL-2, CTLA-4, and GITR, Treg are also functionally influenced by less-selective molecules, among them CD28, CD154, TNF-related cytokine-induced molecule, inducible costimulator, CCR4, CCR8, and CCR5 [69 70 71 72 73 74 ], indicating that multiple mechanisms are probably operative in their education and control. How APC function as Treg instructors represents an understudied but important aspect of Treg activities, and recent evidence suggests that APC coordinate recruitment and/or generation scenarios including Foxp3 expression [61 , 73 , 75 ], but in turn, Treg may dictate APC functions [76 ]. Clearly, Treg cells do not function in isolation, and once activated, APC also may limit Treg-suppressive function following TLR ligation-induced release of IL-6 and/or other molecules [77 ] (Fig. 1) , demonstrating differential roles for APC depending on their activation status. TLR, newly recognized on Treg [78 ], may contribute to the regulation of these suppressor cells in the context of infectious pathogens.

Although the in vitro dependency of Treg suppression on TGF-ß is compelling, immune suppression mediated by Treg in vivo clearly requires TGF-ß, in that administration of an antibody to TGF-ß blocks protection from colitis, otherwise afforded by transfer of a mixture of CD45RBhi and CD4+CD25+CD45RBlow cells [56 ]. Moreover, in a type 1 diabetes model, CD8+ T cells bearing a dominant-negative TßRII transgene were functionally incapable of responding to Treg suppression, resulting in diabetes progression [63 ].

Although the debate over the mechanism of Treg suppression is resolving, the source and pathways by which these Treg cells are generated and developed remain elusive. Previous evidence favored the thymus as the incubator for Treg and suggested that little could be accomplished in attempting to manipulate these cells in the periphery for interventional tactics. However, in exciting new data, it appears that the necessary stimuli by which peripheral CD4+ T cell populations can be converted to functional and phenotypic Treg, at least in vitro, are now being defined [75 , 79 , 80 ]. When coactivated with TCR and TGF-ß, CD4+CD25– T cells begin to express the transcription factor, forkhead/winged helix (Foxp3), which appears to be a master regulator for their transition into CD4+CD25+ T suppressor cells [81 82 83 ]. TCR activation of CD4+ responder T cells in the presence of defining concentrations of TGF-ß does not trigger expansion of small numbers of Treg cells in the population but rather converts the CD4+ responder T cells to CD4+CD25+Foxp3+ T cells, which are not only anergic but also suppress antigen-driven responder cell proliferation. More importantly, transfer of these converted Treg into mice immunized and challenged with house dust-mite allergen resulted in a striking reduction in lung infiltrates, mucus production, and asthma pathogenesis [75 ]. These deliberate mechanisms to drive Treg commitment in peripheral T cells are consonant with recent data, documenting increased numbers of Treg cells bearing TGF-ß associated with control of autoaggressive behavior in vivo [63 ]. With the evolving potential to induce Treg upon demand, it becomes feasible to consider therapeutic manipulation of immunopathologic sequelae. Boosting Treg may control autoimmune diseases and promote transplant survival, whereas reducing Treg may be instrumental in tumor rejection, vaccination, and pathogen clearance.


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CLEARANCE OF APOPTOTIC CELLS IN IMMUNE RESOLUTION
 
In addition to immune suppression by Treg cells, resolution of the host response demands clearance of the inflammatory cells responsible for maintaining and/or amplifying the response, which if excessive, can lead to tissue damage and pathogenesis. Whereas necrotic cell death results in the unleashing of intracellular molecules that contribute to an inflammatory milieu, cells undergoing apoptotic demise expose recognition molecules leading to their speedy clearance by phagocytes before spillage of their cellular contents into the surrounding tissue. Apoptotic cells suppress production of inflammatory mediators such as TNF-{alpha}, IL-1ß, and IL-12 by the engulfing macrophages in vitro and in vivo [84 , 85 ]. However, simple neutrality of apoptotic clearance could never explain why apoptosis-inducing treatments such as UV irradiation and X-rays ameliorate inflammatory conditions [86 , 87 ]. This is because the act of apoptotic cell ingestion is actively anti-inflammatory, as the recognition event triggers a unique regulatory pathway that further dampens inflammation and immunity [84 , 87 ]. Recognition of the phospholipid, phosphatidylserine, newly emergent on the apoptotic cell surface, by a receptor(s) on the phagocytic cell can serve as a switch to direct pro- or anti-inflammatory sequelae and/or the conversion from an innate to an adaptive immune response through the production of TGF-ß, IL-10, and/or prostaglandin E2 (PGE2) [84 , 85 , 87 , 88 ] (Fig. 2 ). Unequivocally, TGF-ß represents one of the central instigators of this anti-inflammatory milieu [84 , 87 ]. In addition to the profiles of T cell and macrophage suppression described above, TGF-ß also stifles Fc receptor for immunoglobulin G-mediated inflammation by down-regulating the common {gamma} subunit in myeloid cells [89 ] and inhibits chemokines, such as monocyte chemoattractant protein-1, to further reduce leukocyte recruitment to the site of inflammation. Not only phagocytosing macrophages but apoptotic T cells themselves spew out latent as well as active TGF-ß [87 ] and IL-10 [88 ] (Fig. 2) . Elevated TGF-ß in the local tissue site, beyond promoting resolution of inflammation, may also contribute to tissue repair and if unchecked, promote fibropathology. Emphasizing the on-off switch analogy, TGF-ß down-regulates expression of CD36, one of the receptors involved in recognition and clearance of apoptotic cells [90 ], which may function to resolve the resolution.



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  		Figure 2. Apoptosis of T cells and their clearance coordinates suppression and resolution of immune responses. T cells, once activated, express enhanced levels of surface molecules/receptors that invoke apoptosis in a process of activation-induced cell death (AICD). Apoptotic T cells flip intracellular phosphatidylserine onto the outer leaflet of their membranes, making them recognizable for clearance by phagocytic cells, and also release TGF-ß as their final suicidal act. Recognition and phagocytosis of apoptotic T cells signal macrophages to spew out substantial TGF-ß, which together with IL-10 and PGE2, mediates immune suppression. Deficiency in TGF-ß results in unresolved inflammation and immunopathologic sequelae. MHC, Major histocompatibility complex.

Introduction of apoptotic cells into an inflammatory lung model reportedly ameliorated inflammatory cytokine production and leukocyte recruitment [85 ]. Furthermore, simple lipid vesicles bearing phosphatidylserine could mimic this therapeutic effect, apparently as a result of their ability to elicit TGF-ß release from lung macrophages. Nonetheless, injection of apoptotic cells into the peritoneal cavity caused immediate neutrophil recruitment [91 ], signifying a rapid but transient, proinflammatory response. It stands to reason that immediate down-regulation of inflammation is not always in the best interest of the host, and there is evidence that macrophages read a complex combination of signals to make this discrimination. In this regard, although presentation of apoptotic cells to macrophages induces a completely disparate panel of cytokines than does engagement of TLR with lipopolysaccharide or other ligands, combinations of these signals elicit temporally complex ensembles of pro- and anti-inflammatory mediators, depending on the ligands and order of addition [92 ]. However, where initial differences in signals and their amplitude may lead the immune response down different paths, all roads lead to TGF-ß in the end [93 ].

T cell apoptosis remains one of the major mechanisms underlying self-immune tolerance and homeostasis, and TGF-ß influences the life and death decisions of T lymphocytes [87 , 93 , 94 ]. The TGF-ß1 null mouse is doubly plagued, as there is an enormous increase in T cell apoptosis, but when faced with this overwhelming phagocytic burden, neither the macrophages nor the apoptotic T cells can release TGF-ß1 to quell the storm. TGF-ß1-deficient T cells manifest spontaneous activation and proliferation, and multiple organs, notably heart and lungs, become invaded by burgeoning numbers of these cells, which continue to accumulate until the organ structure and function are compromised. This inability to clear activated immune cells undergoing apoptosis with the corresponding release of requisite, suppressive molecules amplifies autoaggression and documents the nonredundancy for TGF-ß in this aspect of the immune response. In this deficiency lies the crux of the inability of the mutant mice to resolve their unrelenting and lethal inflammatory response.

Dramatically, injection of anti-CD3 into TGF-ß1 null mice targets the already-activated T cells and amplifies and accelerates their death. As a result of the double-whammy of TGF-ß1 deficiency in this scenario, a sublethal dose of anti-CD3 is lethal in all null mice compared with complete survival of wild-type TGF-ß-sufficient littermates [95 ]. The balance among sufficient apoptosis of activated, "dangerous", and/or damaged lymphocytes and release of sufficient levels of anti-inflammatory cytokines during their clearance are prerequisites to restore homeostasis and function of the immune system. When uncoupled from the secretion of TGF-ß, phagocytosis of apoptotic lymphocytes can no longer prevent the development of uncontrolled inflammation and autoimmune-like diseases.

Defects in apoptotic cell clearance have been directly linked to persistent inflammatory and autoimmune conditions in humans [96 97 98 ]. For example, patients with genetic defects in the phagocyte reduced nicotinamide adenine dinucleotide phosphate-oxidase system, whose neutrophils are resistant to apoptosis and macrophages are severely compromised in their ability to produce anti-inflammatory mediators such as TGF-ß, suffer not only from recurrent, life-threatening infections but must also endure sterile inflammation and chronic granulomatous disease [98 ]. This pathology is most likely a consequence of post-apoptotic secondary necrosis, in addition to the lack of immunosuppression normally generated by successful clearance of apoptotic cells in the first place. In some ways similar to the TGF-ß-deficient mouse, impairment of cell-death pathways, combined with inadequate TGF-ß release associated with clearance, deliver a one-two punch of unchecked inflammation and pathogenesis.


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TGF-ß ALTERS HOST RESPONSE TO PATHOGENS
 
Although the suppressive role of Treg and apoptotic cell clearance are essential in regulation and resolution of innate and adaptive immune responses, excess or uncontrolled suppression may also be problematic, in that tumors, acquired immune deficiencies, and infectious pathogens may benefit from aberrant suppression. Unregulated apoptosis or Treg-mediated suppression may prevent clearance of certain persistent bacterial and viral infections, whereas TLR-dependent blockade of Treg suppression by DC [77 ] may promote pathogen clearance or prolong the host response. Consequently, the host response to certain pathogens may be compromised by a constellation of events associated with suppressive dominance, underscoring the need to understand and regulate not only this powerful population of Treg but also TGF-ß production, secretion, and activation.

Creative pathogens such as obligate intracellular parasites can take advantage of a compromised host response and commandeer the host machinery to benefit their own survival and growth. Able to survive and replicate within the hostile acid environment of the phagolysosome of macrophages, leishmania parasites initially replicate and coexist with the host. Effective resistance to leishmania infection is mediated by Th1 cells, which through the production of IFN-{gamma}, activate macrophages to express elevated levels of iNOS and toxic NO, a molecule with potent ability to kill intracellular parasites [99 100 101 ]. The indispensable nature of iNOS in leishmania infections is most evident in mice deficient in iNOS, which develop nonhealing, disseminated lesions following infection with Leishmania major [102 ], coincident with reduced IFN-{gamma} and increased TGF-ß in the lesions and lymph nodes.

TGF-ß, by its ability to suppress NO production [103 ], inhibit TNF-{alpha} and IFN-{gamma}, and influence T cell differentiation [38 ], is instrumental in determining the outcome of leishmanial infections [101 ]. In fact, leishmania parasites may use TGF-ß as an escape mechanism [104 ]. Using parasite-derived cathepsins to activate TGF-ß, leishmania species may increase local concentrations of active TGF-ß to modulate local iNOS and arginase levels, thereby providing a survival advantage for the parasite [105 ]. Exogenous TGF-ß, whether administered as recombinant protein or via adenoviral vector, promotes leishmania infection in resistant mice, associated with elevated IL-10 [104 , 106 ]. Furthermore, treatment of susceptible strains of mice, such as BALB/c, with antibodies to TGF-ß results not only in a rejuvenated Th1 response, to the detriment of their typical, dominant Th2-nonprotective response, but also resistance to infection [104 , 107 ]. This increased resistance following depletion of TGF-ß could be traced to an elevation in NO [108 ], consistent with the critical influence of TGF-ß during chronic stages of L. major infections. In this same vein, abrogation of TGF-ß signaling by expression of a dominant-negative TßRII transgene in T cells generates a more effective Th1 response to control leishmaniasis in susceptible BALB/c mice, overshadowing their otherwise nonprotective Th2 response [38 ].

However, in the context of this parasitic disease, as in most of its kaleidoscope of activities, TGF-ß is not all bad. Host-derived TGF-ß, by dampening the host response to leishmania, also fosters maintenance of protective immunity. Recently, Treg cells have been implicated in the persistence of cutaneous L. major infection in resistant C57BL/6 mice [109 ], necessary for durable protection. In this parasitic disease, Treg cells, by partially suppressing the protective Th1 response, limit the antiparasitic response, thus enabling maintenance of a residual pocket of parasites necessary for an effective secondary-immune response. Depletion of Treg in resistant mice enhanced Th1 development with elimination of the parasites and loss of protection from secondary challenge. In contrast, adding to the complexity, Treg depletion in susceptible BALB/c mice promoted Th2 development and exacerbated the infection [110 ]. These studies emphasize that contextually, Treg cells are not only essential for controlling parasitic infections but are also critical for maintaining protective immunity and that the outcome of infection hinges on the balance between Treg and effector T cell populations and potentially, the levels of TGF-ß.

To more directly illuminate the involvement of TGF-ß in regulation of infectious disease, the host response to the intracellular parasite L. major was monitored in TGF-ß1 null and wild-type littermates [111 ]. It is striking that in the absence of TGF-ß1, mice were highly resistant to cutaneous infection of the ear dermis, developing smaller lesions (if any) than the wild-type littermates with greatly diminished parasite numbers. Invocation of an embellished defense in the absence of TGF-ß1 was attributed to an effective Th1 response with constitutively elevated IFN-{gamma} and iNOS, yielding high levels of NO and increased parasite-killing capacity. Additionally, arginase levels were dramatically reduced in the mutants as compared with the susceptible wild-type mice, which at this early time-point, preferentially expressed high levels of arginase and diminished iNOS. TGF-ß has been shown to enhance arginase by diverting arginine use from iNOS to arginase, which effectively reduces NO levels and enhances production of polyamines, which promote parasite growth and eventual dissemination of disease [112 ]. Collectively, these studies espouse a critical and nonredundant involvement of TGF-ß1 in the pathogenesis of L. major infection, which may provide insight regarding specific pathways and gene targets that can be manipulated to promote resistance.

TGF-ß has also been incriminated as a preferred hostage for additional pathogens. Trypanosoma parasites reportedly make use of TGF-ß for successful infection, as Trypanosoma cruzi require functional TßRII to facilitate their entry into mammalian cells [113 ] and Trypanosoma brucei induce TGF-ß via the lymphocyte-activating factor [114 ]. Mice depleted of TGF-ß develop fewer lung granulomas following intravenous injection with Schistosoma mansoni eggs as compared with wild-type littermates or heterozygotes [115 ]. However, the few granulomas are larger in size, likely reflecting the absence of TGF-ß-dependent suppression. In addition to parasitic diseases, TGF-ß may also influence bacterial and viral infections [101 ]. TGF-ß has been identified in lung granulomas of tuberculosis patients and is secreted by cultured monocytes from individuals with active tuberculosis [116 ]. Furthermore, natural inhibitors of TGF-ß, decorin, and latency-associated peptide, reversed depressed T cell responses in peripheral blood mononuclear cells from tuberculosis patients and reduced mycobacterial growth in infected monocytes [117 ].

In gram-positive and -negative infections (in autoimmune mice), TGF-ß can adversely affect the outcome [118 ]. Circulating levels of TGF-ß are increased in an experimental model of gram-negative bacterial sepsis [119 ] and in patients with sepsis syndrome [120 ]. The development of gram-negative Providencia rettgeri infection in mice lacking the TGF-ß signaling molecule Smad3 [12 ], the extreme sensitivity of TGF-ß1 null mice to endotoxin shock [121 ], and the development of gastric adenocarcinoma following infection with Heliobacter pylori in mice expressing a dominant-negative TGF-ßRII transgene [122 ] all indicate that functional TGF-ß signaling is inextricably linked to host defense and immunity.

Pathogens, such as Toxoplasma gondii, or structural components of human immunodeficiency virus type 1 (HIV-1) or Mycobacterium tuberculosis can modulate host TGF-ß production and compromise host-defense mechanisms. In viral infections, such as HIV and hepatitis C, induced TGF-ß may penetrate cell-mediated and humoral-immune responses, thus affecting the susceptibility to and progression of disease [101 , 123 ]. Interaction of viral transactivators including tax (human T cell lymphotropic virus 1), tat (HIV-1), and IE1/2 (cytomegalovirus) with the TGF-ß1 promoter triggers TGF-ß1 gene transcription to potentiate persistent infection [123 ] or in the case of Epstein-Barr virus, reactivate infection [124 ]. Not only endogenous cytokine but also exogenous TGF-ß can exacerbate infection and promote disease progression, as evidenced with toxoplasma, mycobacteria, staphylococci, and herpes simplex virus, or be protective, most apparent in malaria [125 ] and listeriosis [126 ]. Opportunistic fungal infections such as candidiasis are also associated with elevated production of active TGF-ß, which can contribute to the development of an effective Th1 response, driving anticandidal resistance [127 ], but of disease progression in the immunocompromised host [128 ], again emphasizing that the immunologic consequences of this cytokine are invariably dependent on context.

Received November 5, 2003; revised December 23, 2003; accepted January 9, 2004.


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REFERENCES
 
    1
  1. Wahl, S. M., Hunt, D. A., Wakefield, L. M., McCartney-Francis, N., Wahl, L. M., Roberts, A. B., Sporn, M. B. (1987) Transforming growth factor type ß induces monocyte chemotaxis and growth factor production Proc. Natl. Acad. Sci. USA 84,5788-5792[Abstract/Free Full Text]
    2. 2
  2. Brandes, M. E., Mai, U. E., Ohura, K., Wahl, S. M. (1991) Type I transforming growth factor-ß receptors on neutrophils mediate chemotaxis to transforming growth factor-ß J. Immunol. 147,1600-1606[Abstract]
    3. 3
  3. Adams, D. H., Hathaway, M., Shaw, J., Burnett, D., Elias, E., Strain, A. J. (1991) Transforming growth factor-ß induces human T lymphocyte migration in vitro J. Immunol. 147,609-612[Abstract]
    4. 4
  4. Wahl, S. M., Allen, J. B., Weeks, B. S., Wong, H. L., Klotman, P. E. (1993) Transforming growth factor ß enhances integrin expression and type IV collagenase secretion in human monocytes Proc. Natl. Acad. Sci. USA 90,4577-4581[Abstract/Free Full Text]
    5. 5
  5. McCartney-Francis, N. L., Frazier-Jessen, M., Wahl, S. M. (1998) TGF-ß: a balancing act Int. Rev. Immunol. 16,553-580[Medline]
    6. 6
  6. Chen, W., Wahl, S. M. (2002) TGF-ß: receptors, signaling pathways and autoimmunity Curr. Dir. Autoimmun. 5,62-91[Medline]
    7. 7
  7. Annes, J. P., Munger, J. S., Rifkin, D. B. (2003) Making sense of latent TGFß activation J. Cell Sci. 116,217-224[Abstract/Free Full Text]
    8. 8
  8. Khalil, N. (1999) TGF-ß: from latent to active Microbes Infect. 1,1255-1263[CrossRef][Medline]
    9. 9
  9. Ashcroft, G. S., Yang, X., Glick, A. B., Weinstein, M., Letterio, J. L., Mizel, D. E., Anzano, M., Greenwell-Wild, T., Wahl, S. M., Deng, C., Roberts, A. B. (1999) Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response Nat. Cell Biol. 1,260-266[CrossRef][Medline]
    10. 10
  10. Roberts, A. B. (1999) TGF-ß signaling from receptors to the nucleus Microbes Infect. 1,1265-1273[CrossRef][Medline]
    11. 11
  11. Weinstein, M., Yang, X., Li, C., Xu, X., Gotay, J., Deng, C. X. (1998) Failure of egg cylinder elongation and mesoderm induction in mouse embryos lacking the tumor suppressor Smad2 Proc. Natl. Acad. Sci. USA 95,9378-9383[Abstract/Free Full Text]
    12. 12
  12. Yang, X., Letterio, J. J., Lechleider, R. J., Chen, L., Hayman, R., Gu, H., Roberts, A. B., Deng, C. (1999) Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-ß EMBO J. 18,1280-1291[CrossRef][Medline]
    13. 13
  13. Shull, M.M., Ormsby, I., Kier, A.B., Pawlowski, S., Diebold, R.J., Yin, M., Allen, R., Sidman, C., Proetzel, B., Calvin, D., Annuniziata, N., Doeschman, T. (1992) Targeted disruption of the mouse transforming growth factor-ß1 gene results in multifocal inflammatory disease Nature 359,693-699[CrossRef][Medline]
    14. 14
  14. Kulkarni, A. B., Huh, C-H., Becker, D., Gerser, A., Lyght, M., Flanders, K. C., Roberts, A. B., Sporn, M. B., Ward, J. M., Karlsson, S. (1993) Transforming growth factor-ß null mutation in mice causes excessive inflammatory response and early death Proc. Natl. Acad. Sci. USA 90,770-774[Abstract/Free Full Text]
    15. 15
  15. Christ, M., McCartney-Francis, N. L., Kulkarni, A. B., Ward, J. M., Mizel, D. E., Mackall, C. L., Gress, R. E., Hines, K. L., Tian, H., Karlsson, S., Wahl, S. M. (1994) Immune dysregulation in TGF-ß1-deficient mice J. Immunol. 153,1936-1946[Abstract]
    16. 16
  16. Hayashi, H., Abdollah, S., Qiu, Y., Cai, J., Xu, Y. Y., Grinnell, B. W., Richardson, M. A., Topper, J. N., Gimbrone, M. A., Jr, Wrana, J. L., Falb, D. (1997) The MAD-related protein Smad7 associates with the TGFß receptor and functions as an antagonist of TGFß signaling Cell 89,1165-1173[CrossRef][Medline]
    17. 17
  17. Imamura, T., Takase, M., Nishihara, A., Oeda, E., Hanai, J., Kawabata, M., Miyazono, K. (1997) Smad6 inhibits signalling by the TGF-ß superfamily Nature 389,622-626[CrossRef][Medline]
    18. 18
  18. Ulloa, L., Doody, J., Massague, J. (1999) Inhibition of transforming growth factor-ß/Smad signalling by the interferon-{gamma}/STAT pathway Nature 397,710-713[CrossRef][Medline]
    19. 19
  19. Arsura, M., Wu, M., Sonenshein, G. E. (1996) TGF ß 1 inhibits NF-{kappa} B/Rel activity inducing apoptosis of B cells: transcriptional activation of I {kappa} B {alpha} Immunity 5,31-40[CrossRef][Medline]
    20. 20
  20. Hanafusa, H., Ninomiya-Tsuji, J., Masuyama, N., Nishita, M., Fujisawa, J., Shibuya, H., Matsumoto, K., Nishida, E. (1999) Involvement of the p38 mitogen-activated protein kinase pathway in transforming growth factor-ß-induced gene expression J. Biol. Chem. 274,27161-27167[Abstract/Free Full Text]
    21. 21
  21. Derynck, R., Zhang, Y. E. (2003) Smad-dependent and Smad-independent pathways in TGF-ß family signalling Nature 425,577-584[CrossRef][Medline]
    22. 22
  22. Sporn, M. B. (1999) TGF-ß: 20 years and counting Microbes Infect. 1,1251-1253[CrossRef][Medline]
    23. 23
  23. Wahl, S. M. (1994) Transforming growth factor: the good, the bad, and the ugly J. Exp. Med. 180,1587-1590[Free Full Text]
    24. 24
  24. Brandes, M. E., Allen, J. B., Ogawa, Y., Wahl, S. M. (1991) Transforming growth factor ß 1 suppresses acute and chronic arthritis in experimental animals J. Clin. Invest. 87,1108-1113
    25. 25
  25. Allen, J. B., Manthey, C. L., Hand, A. R., Ohura, K., Ellingsworth, L., Wahl, S. M. (1990) Rapid onset synovial inflammation and hyperplasia induced by transforming growth factor ß J. Exp. Med. 171,231-247[Abstract/Free Full Text]
    26. 26
  26. Border, W. A., Ruoslahti, E. (1992) Transforming growth factor-ß in disease: the dark side of tissue repair J. Clin. Invest. 90,1-7
    27. 27
  27. Bogdan, C., Nathan, C. (1993) Modulation of macrophage function by transforming growth factor ß, interleukin-4, and interleukin-10 Ann. N. Y. Acad. Sci. 685,713-739[Medline]
    28. 28
  28. Chen, W., Wahl, S. M. (1999) Manipulation of TGF-ß to control autoimmune and chronic inflammatory diseases Microbes Infect. 1,1367-1380[CrossRef][Medline]
    29. 29
  29. Weiner, H. L., Friedman, A., Miller, A., Khoury, S. J., al-Sabbagh, A., Santos, L., Sayegh, M., Nussenblatt, R. B., Trentham, D. E., Hafler, D. A. (1994) Oral tolerance: immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens Annu. Rev. Immunol. 12,809-837[CrossRef][Medline]
    30. 30
  30. Chen, Y., Kuchroo, V. K., Inobe, J., Hafler, D. A., Weiner, H. L. (1994) Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis Science 265,1237-1240[Abstract/Free Full Text]
    31. 31
  31. Weiner, H. L. (2000) Oral tolerance, an active immunologic process mediated by multiple mechanisms J. Clin. Invest. 106,935-937[Medline]
    32. 32
  32. Chen, W. J., Jin, W., Cook, M., Weiner, H. L., Wahl, S. M. (1998) Oral delivery of group A streptococcal cell walls augments circulating TGF-ß and suppresses SCW arthritis J. Immunol. 161,6297-6304[Abstract/Free Full Text]
    33. 33
  33. Strober, W., Kelsall, B., Marth, T. (1998) Oral tolerance J. Clin. Immunol. 18,1-30[CrossRef][Medline]
    34. 34
  34. Wahl, S. M., Chen, W. (2003) TGF-ß: how tolerant can it be? Immunol. Res. 28,167-179[CrossRef][Medline]
    35. 35
  35. Kehrl, J. H., Wakefield, L. M., Roberts, A. B., Jakowelw, S., Alvarez-Mon, M., Derynck, R., Sporn, M. B., Fauci, A. S. (1986) Production of transforming growth factor ß by human T lymphocytes and its potential role in the regulation of T cell growth J. Exp. Med. 163,1037-1050[Abstract/Free Full Text]
    36. 36
  36. Chen, W., Wahl, S. M. (2003) TGF-ß: the missing link in CD4(+)CD25(+) regulatory T cell-mediated immunosuppression Cytokine Growth Factor Rev. 14,85-89[CrossRef][Medline]
    37. 37
  37. Lucas, P. J., Kim, S. J., Melby, S. J., Gress, R. E. (2000) Disruption of T cell homeostasis in mice expressing a T cell-specific dominant negative transforming growth factor ß II receptor J. Exp. Med. 191,1187-1196[Abstract/Free Full Text]
    38. 38
  38. Gorelik, L., Constant, S., Flavell, R. A. (2002) Mechanism of transforming growth factor ß-induced inhibition of T helper type 1 differentiation J. Exp. Med. 195,1499-1505[Abstract/Free Full Text]
    39. 39
  39. Capocasale, R. J., Lamb, R. J., Vonderheid, E. C., Fox, F. E., Rook, A. H., Nowell, P. C., Moore, J. S. (1995) Reduced surface expression of transforming growth factor ß receptor type II in mitogen-activated T cells from Sezary patients Proc. Natl. Acad. Sci. USA 92,5501-5505[Abstract/Free Full Text]
    40. 40
  40. Seder, R. A., Paul, W. E. (1994) Acquisition of lymphokine-producing phenotype by CD4+ T cells Annu. Rev. Immunol. 12,635-673[CrossRef][Medline]
    41. 41
  41. Gorelik, L., Fields, P. E., Flavell, R. A. (2000) Cutting edge: TGF-ß inhibits Th type 2 development through inhibition of GATA-3 expression J. Immunol. 165,4773-4777[Abstract/Free Full Text]
    42. 42
  42. Cerwnka, A., Kovar, H., Majdic, O., Holter, W. (1996) Fas- and activation-induced apoptosis are reduced in human T cells preactivated in the presence of TGF-ß1 J. Immunol. 156,459-464[Abstract]
    43. 43
  43. Lee, H. M., Rich, S. (1991) Co-stimulation of T cell proliferation by transforming growth factor-ß1 J. Immunol. 147,1127-1133[Abstract]
    44. 44
  44. Chen, C. R., Kang, Y., Massague, J. (2001) Defective repression of c-myc in breast cancer cells: a loss at the core of the transforming growth factor ß growth arrest program Proc. Natl. Acad. Sci. USA 98,992-999[Abstract/Free Full Text]
    45. 45
  45. Nakao, A., Afrakhte, M., Moren, A., Nakayama, T., Christian, J. L., Heuchel, R., Itoh, S., Kawabata, M., Heldin, N. E., Heldin, C. H., ten Dijke, P. (1997) Identification of Smad7, a TGFß-inducible antagonist of TGF-ß signalling Nature 389,631-635[CrossRef][Medline]
    46. 46
  46. Strober, W., Kesall, B., Fuss, I., Marth, T., Ludviksson, B., Ehrhardt, R., Neurath, M. (1997) Reciprocal IFN-{gamma} and TGF-ß response regulate the occurrence of mucosal inflammation Immunol. Today 18,61-64[CrossRef][Medline]
    47. 47
  47. Lee, Y-J., Han, Y., Lu, H-T., Nguyen, V., Qin, H., Howe, P. H., Hocevar, B. A., Boss, J. M., Ransohoff, R. M., Benveniste, E. N. (1997) TGF-ß suppresses IFN-{gamma} induction of class II MHC gene expression by inhibition class II transactivator messenger RNA expression J. Immunol. 158,2065-2075[Abstract]
    48. 48
  48. Bright, J. J., Sriram, S. (1998) TGF-ß inhibits IL-12-induced activation of Jak-STAT pathway in T lymphocytes J. Immunol. 161,1772-1777[Abstract/Free Full Text]
    49. 49
  49. Gorham, J. D., Guler, M. L., Fenoglio, D., Gubler, U., Murphy, K. M. (1998) Low dose TGF-ß attenuates IL-12 responsiveness in murine Th cells J. Immunol. 161,1664-1670[Abstract/Free Full Text]
    50. 50
  50. McCartney-Francis, N. L., Wahl, S. M. (2002) Dysregulation of IFN-{gamma} signaling pathways in the absence of TGF-ß 1 J. Immunol. 169,5941-5947[Abstract/Free Full Text]
    51. 51
  51. Itoh, M., Takahashi, T., Sakaguchi, N., Kuniyasu, Y., Shimizu, J., Otsuka, F., Sakaguchi, S. (1999) Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance J. Immunol. 162,5317-5326[Abstract/Free Full Text]
    52. 52
  52. Shevach, E. M. (2002) CD4+ CD25+ suppressor T cells: more questions than answers Nat. Rev. Immunol. 2,389-400[Medline]
    53. 53
  53. Groux, H. (2001) An overview of regulatory T cells Microbes Infect. 3,883-889[CrossRef][Medline]
    54. 54
  54. Jonuleit, H., Adema, G., Schmitt, E. (2003) Immune regulation by regulatory T cells: implications for transplantation Transpl. Immunol. 11,267-276[CrossRef][Medline]
    55. 55
  55. Chatenoud, L., Salomon, B., Bluestone, J. A. (2001) Suppressor T cells—they’re back and critical for regulation of autoimmunity! Immunol. Rev. 182,149-163[CrossRef][Medline]
    56. 56
  56. Read, S., Malmstrom, V., Powrie, F. (2000) 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[Abstract/Free Full Text]
    57. 57
  57. Salomon, B., Lenschow, D. J., Rhee, L., Ashourian, N., Singh, B., Sharpe, A., Bluestone, J. A. (2000) B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes Immunity 12,431-440[CrossRef][Medline]
    58. 58
  58. Takahashi, T., Tagami, T., Yamazaki, S., Uede, T., Shimizu, J., Sakaguchi, N., Mak, T. W., Sakaguchi, S. (2000) Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4 J. Exp. Med. 192,303-310[Abstract/Free Full Text]
    59. 59
  59. Shimizu, J., Yamazaki, S., Takahashi, T., Ishida, Y., Sakaguchi, S. (2002) Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance Nat. Immunol. 3,135-142[CrossRef][Medline]
    60. 60
  60. McHugh, R. S., Whitters, M. J., Piccirillo, C. A., Young, D. A., Shevach, E. M., Collins, M., Byrne, M. C. (2002) CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor Immunity 16,311-323[CrossRef][Medline]
    61. 61
  61. Powrie, F., Maloy, K. J. (2003) Immunology. Regulating the regulators Science 299,1030-1031[Abstract/Free Full Text]
    62. 62
  62. Nakamura, K., Kitani, A., Strober, W. (2001) Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor ß J. Exp. Med. 194,629-644[Abstract/Free Full Text]
    63. 63
  63. Green, E. A., Gorelik, L., McGregor, C. M., Tran, E. H., Flavell, R. A. (2003) CD4+CD25+ T regulatory cells control anti-islet CD8+ T cells through TGF-{ß}–TGF-{ß} receptor interactions in type 1 diabetes Proc. Natl. Acad. Sci. USA 100,10878-10883[Abstract/Free Full Text]
    64. 64
  64. Oida, T., Zhang, X., Goto, M., Hachimura, S., Totsuka, M., Kaminogawa, S., Weiner, H. L. (2003) CD4+CD25– T cells that express latency-associated peptide on the surface suppress CD4+CD45RBhigh-induced colitis by a TGF-ß-dependent mechanism J. Immunol. 170,2516-2522[Abstract/Free Full Text]
    65. 65
  65. Piccirillo, C. A., Letterio, J. J., Thornton, A. M., McHugh, R. S., Mamura, M., Mizuhara, H., Shevach, E. M. (2002) CD4(+)CD25(+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor ß1 production and responsiveness J. Exp. Med. 196,237-246[Abstract/Free Full Text]
    66. 66
  66. Chen, W., Jin, W., Wahl, S. M. (1998) Engagement of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) induces transforming growth factor ß (TGF-ß) production by murine CD4(+) T cells J. Exp. Med. 188,1849-1857[Abstract/Free Full Text]
    67. 67
  67. Gomes, N. A., Gattass, C. R., Barreto-De-Souza, V., Wilson, M. E., DosReis, G. A. (2000) TGF-ß mediates CTLA-4 suppression of cellular immunity in murine kalaazar J. Immunol. 164,2001-2008[Abstract/Free Full Text]
    68. 68
  68. Schneider, H., Mandelbrot, D. A., Greenwald, R. J., Ng, F., Lechler, R., Sharpe, A. H., Rudd, C. E. (2002) Cutting edge: CTLA-4 (CD152) differentially regulates mitogen-activated protein kinases (extracellular signal-regulated kinase and c-Jun N-terminal kinase) in CD4(+) T cells from receptor/ligand-deficient mice J. Immunol. 169,3475-3479[Abstract/Free Full Text]
    69. 69
  69. Bystry, R. S., Aluvihare, V., Welch, K. A., Kallikourdis, M., Betz, A. G. (2001) B cells and professional APCs recruit regulatory T cells via CCL4 Nat. Immunol. 2,1126-1132[CrossRef][Medline]
    70. 70
  70. Malek, T. R., Yu, A., Vincek, V., Scibelli, P., Kong, L. (2002) CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rß-deficient mice. Implications for the nonredundant function of IL-2 Immunity 17,167-178[CrossRef][Medline]
    71. 71
  71. Kumanogoh, A., Wang, X., Lee, I., Watanabe, C., Kamanaka, M., Shi, W., Yoshida, K., Sato, T., Habu, S., Itoh, M., Sakaguchi, N., Sakaguchi, S., Kikutani, H. (2001) Increased T cell autoreactivity in the absence of CD40-CD40 ligand interactions: a role of CD40 in regulatory T cell development J. Immunol. 166,353-360[Abstract/Free Full Text]
    72. 72
  72. Akbari, O., Freeman, G. J., Meyer, E. H., Greenfield, E. A., Chang, T. T., Sharpe, A. H., Berry, G., DeKruyff, R. H., Umetsu, D. T. (2002) Antigen-specific regulatory T cells develop via the ICOS–ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity Nat. Med. 8,1024-1032[CrossRef][Medline]
    73. 73
  73. D’Ambrosio, D., Sinigaglia, F., Adorini, L. (2003) Special attractions for suppressor T cells Trends Immunol. 24,122-126[CrossRef][Medline]
    74. 74
  74. Green, E. A., Choi, Y., Flavell, R. A. (2002) Pancreatic lymph node-derived CD4(+)CD25(+) Treg cells: highly potent regulators of diabetes that require TRANCE-RANK signals Immunity 16,183-191[CrossRef][Medline]
    75. 75
  75. Chen, W., Jin, W., Hardegen, N., Lei, K., Li, L., Marinos, N., McGrady, G., Wahl, S. M. (2003) Conversion of peripheral CD4+CD25– regulatory T cells by TGF-ß induction of transcription factor Foxp3 J. Exp. Med. 198,1875-1886[Abstract/Free Full Text]
    76. 76
  76. Takeuchi, M., Alard, P., Streilein, J. W. (1998) TGF-ß promotes immune deviation by altering accessory signals of antigen-presenting cells J. Immunol. 160,1589-1597[Abstract/Free Full Text]
    77. 77
  77. Pasare, C., Medzhitov, R. (2003) Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells Science 299,1033-1036[Abstract/Free Full Text]
    78. 78
  78. Caramalho, I., Lopes-Carvalho, T., Ostler, D., Zelenay, S., Haury, M., Demengeot, J. (2003) Regulatory T cells selectively express Toll-like receptors and are activated by lipopolysaccharide J. Exp. Med. 197,403-411[Abstract/Free Full Text]
    79. 79
  79. Chen, Z. M., O’Shaughnessy, M. J., Gramaglia, I., Panoskaltsis-Mortari, A., Murphy, W. J., Narula, S., Roncarolo, M. G., Blazar, B. R. (2003) IL-10 and TGF-ß induce alloreactive CD4+CD25– T cells to acquire regulatory cell function Blood 101,5076-5083[Abstract/Free Full Text]
    80. 80
  80. Zheng, S. G., Gray, J. D., Ohtsuka, K., Yamagiwa, S., Horwitz, D. A. (2002) Generation ex vivo of TGF-ß-producing regulatory T cells from CD4+CD25– precursors J. Immunol. 169,4183-4189[Abstract/Free Full Text]
    81. 81
  81. Fontenot, J. D., Gavin, M. A., Rudensky, A. Y. (2003) Foxp3 programs the development and function of CD4(+)CD25(+) regulatory T cells Nat. Immunol. 4,330-336[CrossRef][Medline]
    82. 82
  82. Ramsdell, F. (2003) Foxp3 and natural regulatory T cells. Key to a cell lineage? Immunity 19,165-168[CrossRef][Medline]
    83. 83
  83. Hori, S., Nomura, T., Sakaguchi, S. (2003) Control of regulatory T cell development by the transcription factor Foxp3 Science 299,1057-1061[Abstract/Free Full Text]
    84. 84
  84. Fadok, V. A., Bratton, D. L., Konowal, A., Freed, P. W., Westcott, J. Y., Henson, P. M. (1998) Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-ß, PGE2, and PAF J. Clin. Invest. 101,890-898[Medline]
    85. 85
  85. Huynh, M. L., Fadok, V. A., Henson, P. M. (2002) Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-ß1 secretion and the resolution of inflammation J. Clin. Invest. 109,41-50[CrossRef][Medline]
    86. 86
  86. Abel, E. A. (1999) Phototherapy: UVB and PUVA Cutis 64,339-342[Medline]
    87. 87
  87. Chen, W., Frank, M. E., Jin, W., Wahl, S. M. (2001) TGF-ß released by apoptotic T cells contributes to an immunosuppressive milieu Immunity 14,715-725[CrossRef][Medline]
    88. 88
  88. Voll, R. E., Herrmann, M., Roth, E. A., Stach, C., Kalden, J. R., Girkontaite, I. (1997) Immunosuppressive effects of apoptotic cells Nature 390,350-351[CrossRef][Medline]
    89. 89
  89. Tridandapani, S., Wardrop, R., Baran, C. P., Wang, Y., Opalek, J. M., Caligiuri, M. A., Marsh, C. B. (2003) TGF-ß 1 suppresses [correction of supresses] myeloid Fc {gamma} receptor function by regulating the expression and function of the common {gamma}-subunit J. Immunol. 170,4572-4577[Abstract/Free Full Text]
    90. 90
  90. Han, J., Hajjar, D. P., Tauras, J. M., Feng, J., Gotto, A. M., Jr, Nicholson, A. C. (2000) Transforming growth factor-ß1 (TGF-ß1) and TGF-ß2 decrease expression of CD36, the type B scavenger receptor, through mitogen-activated protein kinase phosphorylation of peroxisome proliferator-activated receptor-{gamma} J. Biol. Chem. 275,1241-1246[Abstract/Free Full Text]
    91. 91
  91. Misawa, R., Kawagishi, C., Watanabe, N., Kobayashi, Y. (2001) Infiltration of neutrophils following injection of apoptotic cells into the peritoneal cavity Apoptosis 6,411-417[CrossRef][Medline]
    92. 92
  92. Lucas, M., Stuart, L. M., Savill, J., Lacy-Hulbert, A. (2003) Apoptotic cells and innate immune stimuli combine to regulate macrophage cytokine secretion J. Immunol. 171,2610-2615[Abstract/Free Full Text]
    93. 93
  93. Wahl, S. M., Orenstein, J. M., Chen, W. (2000) TGF-ß influences the life and death decisions of T lymphocytes Cytokine Growth Factor Rev. 11,71-79[CrossRef][Medline]
    94. 94
  94. Chen, W., Jin, W., Tian, H., Sicurello, P., Frank, M., Orenstein, J. M., Wahl, S. M. (2001) Requirement for transforming growth factor ß1 in controlling T cell apoptosis J. Exp. Med. 194,439-453[Abstract/Free Full Text]
    95. 95
  95. Chen, W., Jin, W., Frank, M., Wahl, S. M. (2001) Lethal effect of anti-CD3 antibody in mice lacking TGF-ß 1 FASEB J. 15,A1045(abstract).
    96. 96
  96. Taylor, P. R., Carugati, A., Fadok, V. A., Cook, H. T., Andrews, M., Carroll, M. C., Savill, J. S., Henson, P. M., Botto, M., Walport, M. J. (2000) A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo J. Exp. Med. 192,359-366[Abstract/Free Full Text]
    97. 97
  97. Botto, M., Dell’Agnola, C., Bygrave, A. E., Thompson, E. M., Cook, H. T., Petry, F., Loos, M., Pandolfi, P. P., Walport, M. J. (1998) Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies Nat. Genet. 19,56-59[CrossRef][Medline]
    98. 98
  98. Brown, J. R., Goldblatt, D., Buddle, J., Morton, L., Thrasher, A. J. (2003) Diminished production of anti-inflammatory mediators during neutrophil apoptosis and macrophage phagocytosis in chronic granulomatous disease (CGD) J. Leukoc. Biol. 73,591-599[Abstract/Free Full Text]
    99. 99
  99. Belkaid, Y. (2003) The role of CD4+CD25+ regulatory T cells in Leishmania infection Expert Opin. Biol. Ther. 3,875-885[CrossRef][Medline]
    100. 100
  100. Sacks, D., Noben-Trauth, N. (2002) The immunology of susceptibility and resistance to Leishmania major in mice Nat. Rev. Immunol. 2,845-858[CrossRef][Medline]
    101. 101
  101. Reed, S. G. (1999) TGF-ß in infections and infectious diseases Microbes Infect. 1,1313-1325[CrossRef][Medline]
    102. 102
  102. Diefenbach, A., Schindler, H., Donhauser, N., Lorenz, E., Laskay, T., MacMicking, J., Rollinghoff, M., Gresser, I., Bogdan, C. (1998) Type 1 interferon (IFN{alpha}/ß) and type 2 nitric oxide synthase regulate the innate immune response to a protozoan parasite Immunity 8,77-87[CrossRef][Medline]
    103. 103
  103. Vodovotz, Y., Bogdan, C., Paik, J., Xie, Q. W., Nathan, C. (1993) Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor ß J. Exp. Med. 178,605-613[Abstract/Free Full Text]
    104. 104
  104. Barral-Netto, M., Barral, A. (1994) Transforming growth factor-ß in tegumentary leishmaniasis Braz. J. Med. Biol. Res. 27,1-9[Medline]
    105. 105
  105. Gantt, K. R., Schultz-Cherry, S., Rodriguez, N., Jeronimo, S. M., Nascimento, E. T., Goldman, T. L., Recker, T. J., Miller, M. A., Wilson, M. E. (2003) Activation of TGF-ß by Leishmania chagasi: importance for parasite survival in macrophages J. Immunol. 170,2613-2620[Abstract/Free Full Text]
    106. 106
  106. Wilson, M. E., Young, B. M., Davidson, B. L., Mente, K. A., McGowan, S. E. (1998) The importance of TGF-ß in murine visceral leishmaniasis J. Immunol. 161,6148-6155[Abstract/Free Full Text]
    107. 107
  107. Barral-Netto, M., Barral, A., Rownell, C. E., Skeiky, Y. A. W., Ellingsworth, L. R., Twardzik, D. R., Reed, S. G. (1992) Transforming growth factor-ß in leishmanial infection: a parasite mechanism Science 257,545-548[Abstract/Free Full Text]
    108. 108
  108. Li, J., Hunter, C. A., Farrell, J. P. (1999) Anti-TGF-ß treatment promotes rapid healing of Leishmania major infection in mice by enhancing in vivo nitric oxide production J. Immunol. 162,974-979[Abstract/Free Full Text]
    109. 109
  109. Belkaid, Y., Piccirillo, C. A., Mendez, S., Shevach, E. M., Sacks, D. L. (2002) CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity Nature 420,502-507[CrossRef][Medline]
    110. 110
  110. Aseffa, A., Gumy, A., Launois, P., MacDonald, H. R., Louis, J. A., Tacchini-Cottier, F. (2002) The early IL-4 response to Leishmania major and the resulting Th2 cell maturation steering progressive disease in BALB/c mice are subject to the control of regulatory CD4+CD25+ T cells J. Immunol. 169,3232-3241[Abstract/Free Full Text]
    111. 111
  111. McCartney-Francis, N., Belkaid, Y., Jin, W., Wahl, S. M. (2002) TGF-ß deficiency promotes resistance to cutaneous leishmaniasis FASEB J. 15,A1071(abstract).
    112. 112
  112. Vincendeau, P., Gobert, A. P., Daulouede, S., Moynet, D., Mossalayi, M. D. (2003) Arginases in parasitic diseases Trends Parasitol. 19,9-12[CrossRef][Medline]
    113. 113
  113. Ming, M., Ewen, M. E., Pereira, M. E. (1995) Trypanosome invasion of mammalian cells requires activation of the TGF ß signaling pathway Cell 82,287-296[CrossRef][Medline]
    114. 114
  114. Olsson, T., Bakhiet, M., Hojeberg, B., Ljungdahl, A., Edlund, C., Andersson, G., Ekre, H. P., Fung-Leung, W. P., Mak, T., Wigzell, H., et al (1993) CD8 is critically involved in lymphocyte activation by a T. brucei brucei-released molecule Cell 72,715-727[CrossRef][Medline]
    115. 115
  115. Wahl, S. M., Frazier-Jessen, M., Jin, W. W., Kopp, J. B., Sher, A., Cheever, A. W. (1997) Cytokine regulation of schistosome-induced granuloma and fibrosis Kidney Int. 51,1370-1375[Medline]
    116. 116
  116. Toossi, Z., Gogate, P., Shiratsuchi, H., Young, T., Ellner, J. J. (1995) Enhanced production of TGF-ß by blood monocytes from patients with active tuberculosis and presence of TGF-ß in tuberculous granulomatous lung lesions J. Immunol. 154,465-473[Abstract]
    117. 117
  117. Hirsch, C. S., Ellner, J. J., Blinkhorn, R., Toossi, Z. (1997) In vitro restoration of T cell responses in tuberculosis and augmentation of monocyte effector function against Mycobacterium tuberculosis by natural inhibitors of transforming growth factor ß Proc. Natl. Acad. Sci. USA 94,3926-3931[Abstract/Free Full Text]
    118. 118
  118. Lowrance, J. H., O’Sullivan, F. X., Caver, T. E., Waegell, W., Gresham, H. D. (1994) Spontaneous elaboration of transforming growth factor ß suppresses host defense against bacterial infection in autoimmune MRL/lpr mice J. Exp. Med. 180,1693-1703[Abstract/Free Full Text]
    119. 119
  119. Ahmad, S., Choudhry, M. A., Shankar, R., Sayeed, M. M. (1997) Transforming growth factor-ß negatively modulates T-cell responses in sepsis FEBS Lett. 402,213-218[CrossRef][Medline]
    120. 120
  120. Marie, C., Cavaillon, J. M., Losser, M. R. (1996) Elevated levels of circulating transforming growth factor-ß 1 in patients with the sepsis syndrome Ann. Intern. Med. 125,520-521[Free Full Text]
    121. 121
  121. McCartney-Francis, N., Jin, W., Wahl, S. M. (2004) Aberrant toll receptor expression and endotoxin hypersensitivity in mice lacking a functional TGF-ß1 signaling pathway J Immunol. 172,3814-3821[Abstract/Free Full Text]
    122. 122
  122. Hahm, K. B., Lee, K. M., Kim, Y. B., Hong, W. S., Lee, W. H., Han, S. U., Kim, M. W., Ahn, B. O., Oh, T. Y., Lee, M. H., Green, J., Kim, S. J. (2002) Conditional loss of TGF-ß signalling leads to increased susceptibility to gastrointestinal carcinogenesis in mice Aliment. Pharmacol. Ther. 16(Suppl. 2),115-127
    123. 123
  123. Wahl, S. M., Allen, J. B., McCartney-Francis, N., Morganti-Kossmann, M. C., Kossmann, T., Ellingsworth, L., Mai, U. E., Mergenhagen, S. E., Orenstein, J. M. (1991) Macrophage- and astrocyte-derived transforming growth factor ß as a mediator of central nervous system dysfunction in acquired immune deficiency syndrome J. Exp. Med. 173,981-991[Abstract/Free Full Text]
    124. 124
  124. Fitzpatrick, D. R., Bielefeldt-Ohmann, H. (1999) Transforming growth factor ß in infectious disease: always there for the host and the pathogen Trends Microbiol. 7,232-236[CrossRef][Medline]
    125. 125
  125. Omer, F. M., Riley, E. M. (1998) Transforming growth factor ß production is inversely correlated with severity of murine malaria infection J. Exp. Med. 188,39-48[Abstract/Free Full Text]
    126. 126
  126. Nakane, A., Asano, M., Sasaki, S., Nishikawa, S., Miura, T., Kohanawa, M., Minagawa, T. (1996) Transforming growth factor ß is protective in host resistance against Listeria monocytogenes infection in mice Infect. Immun. 64,3901-3904[Abstract]
    127. 127
  127. Spaccapelo, R., Romani, L., Tonnetti, L., Cenci, E., Mencacci, A., Del Sero, G., Tognellini, R., Reed, S. G., Puccetti, P., Bistoni, F. (1995) TGF-ß is important in determining the in vivo patterns of susceptibility or resistance in mice infected with Candida albicans J. Immunol. 155,1349-1360[Abstract]
    128. 128
  128. Walsh, T. J., Groll, A. H. (1999) Emerging fungal pathogens: evolving challenges to immunocompromised patients for the twenty-first century Transpl. Infect. Dis. 1,247-261[CrossRef][Medline]



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