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Published online before print February 13, 2004
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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 |
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 TOP ABSTRACT INTRODUCTIONTGF-ß AS AN INHIBITOR...ORAL TOLERANCET CELL TARGETS OF...Treg CELLSCLEARANCE OF APOPTOTIC CELLS...TGF-ß ALTERS HOST...REFERENCES |
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Key Words: immunoregulation • apoptosis • leishmania
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONTGF-ß AS AN INHIBITOR...ORAL TOLERANCET CELL TARGETS OF...Treg CELLSCLEARANCE OF APOPTOTIC CELLS...TGF-ß ALTERS HOST...REFERENCES |
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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-
(IFN-) 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-
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 
(TNF-), 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 |
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TOPABSTRACTINTRODUCTIONTGF-ß AS AN INHIBITOR...ORAL TOLERANCET CELL TARGETS OF...Treg CELLSCLEARANCE OF APOPTOTIC CELLS...TGF-ß ALTERS HOST...REFERENCES |
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ORAL TOLERANCE |
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TOPABSTRACTINTRODUCTIONTGF-ß AS AN INHIBITOR...ORAL TOLERANCET CELL TARGETS OF...Treg CELLSCLEARANCE OF APOPTOTIC CELLS...TGF-ß ALTERS HOST...REFERENCES |
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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. |
T CELL TARGETS OF TGF-ß SUPPRESSION |
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TOPABSTRACTINTRODUCTIONTGF-ß AS AN INHIBITOR...ORAL TOLERANCET CELL TARGETS OF...Treg CELLSCLEARANCE OF APOPTOTIC CELLS...TGF-ß ALTERS HOST...REFERENCES |
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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- and TGF-ß, which involves IFN- enhancement of inhibitory Smad7 expression to block TGF-ß signaling [45
, 46
]. In turn, TGF-ß may directly inhibit IFN- as well as IL-2 production by T cells or indirectly target IFN- 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- and TGF-ß, there is a profound augmentation of IFN- 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 |
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TOPABSTRACTINTRODUCTIONTGF-ß AS AN INHIBITOR...ORAL TOLERANCET CELL TARGETS OF...Treg CELLSCLEARANCE OF APOPTOTIC CELLS...TGF-ß ALTERS HOST...REFERENCES |
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(IL-2R) 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. 4ß7+ Treg might preferentially home to mucosal sites and convert CD4+ T cells into IL-10-producing Tr1-like cells, whereas 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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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 |
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TOPABSTRACTINTRODUCTIONTGF-ß AS AN INHIBITOR...ORAL TOLERANCET CELL TARGETS OF...Treg CELLSCLEARANCE OF APOPTOTIC CELLS...TGF-ß ALTERS HOST...REFERENCES |
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, 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 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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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 |
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TOPABSTRACTINTRODUCTIONTGF-ß AS AN INHIBITOR...ORAL TOLERANCET CELL TARGETS OF...Treg CELLSCLEARANCE OF APOPTOTIC CELLS...TGF-ß ALTERS HOST...REFERENCES |
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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-, 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- and increased TGF-ß in the lesions and lymph nodes.
TGF-ß, by its ability to suppress NO production [103
], inhibit TNF- and IFN-, 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- 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 |
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TOPABSTRACTINTRODUCTIONTGF-ß AS AN INHIBITOR...ORAL TOLERANCET CELL TARGETS OF...Treg CELLSCLEARANCE OF APOPTOTIC CELLS...TGF-ß ALTERS HOST...REFERENCES |
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