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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Curr Opin Pharmacol. Author manuscript; available in PMC 2010 August 1.
Published in final edited form as:
PMCID: PMC2730990

TGF-β can leave you breathless


Transforming growth factor-beta (TGF-β), a ubiquitous and multifunctional cytokine, is central to the evolution and modulation of host defense. Early on, TGF-β was recognized for its chemotactic and pro-inflammatory properties, but then identification of its powerful suppressive activities focused attention on dissecting its mechanisms of immune inhibition. Just as quickly as TGF-β-mediated regulation of a population of CD4+CD25+Foxp3+ regulatory T cells became the rage, a surprising finding that TGF-β was the impetus behind a subset of pro-inflammatory T helper(Th)17 cells brought back a re-emphasis on its broader ability to dictate inflammatory events. Emerging evidence indicates that much remains to be discovered regarding the complex and intertwined roles of TGF-β in inflammation, T cell lineage commitment, antibody generation, immune suppression and tolerance. While it may appear that TGF-β has multiple, ill-defined, contradictory and overlapping modes of activity that are impossible to unravel, the current excitement for dissecting how TGF-β controls immunity defines a challenge worthy of pursuit. The lung is particularly vulnerable to the influences of TGF-β, which is produced by its immune and non-immune cell populations. In its absence, lung pathology becomes lethal, whereas TGF-β overproduction also has untoward consequences, potentially leaving one breathless, and underscoring the paradoxical, but essential contribution of TGF-β to tissue and immune homeostasis.

Keywords: asthma, inflammation, immune suppression, Th17, Treg, Th2


TGF-β is recognized as a staunch supporter of peripheral tolerance to self-antigens and innocuous allergens and in suppression of excessive immune responses detrimental to the host [1]. Discovered nearly 30 years ago [2], TGF-β now represents the prototypic member of a superfamily of structurally and functionally-related peptides that affect many different cellular processes. The three mammalian isoforms of TGF-β(TGF-β1-3), encoded by separate genes, are naturally occurring in most tissues, but TGF-β1 is dominant in the immune system. Both structural and immune cells are capable of secreting TGF-β in a latent form and expressing TGF-β receptors. Once activated, a critical step in TGF-β actions, the peptide binds to a heterodimeric receptor complex(TβR) consisting of type I and II transmembrane serine/threonine kinase subunits, activates Smad-dependent signaling pathways, and thus regulates target gene expression. Recently, additional proteins, namely phosphatidylinositol-3 kinase, mitogen-activated protein kinases, PP2A phosphatase, Rho family proteins, and epithelial polarity protein Par6, have been linked to Smad-independent TGF-β signaling [3].

The vital role of TGF-β in development and immune regulation is illustrated by the fact that ~50% of TGF-β1 null mice die in utero and the remainder succumb to uncontrolled multifocal lymphoproliferative disorders, including T-helper(Th)1-mediated pulmonary inflammation and compromised respiratory function by 3-5weeks of age(Fig. 1A,B). Unchecked T cell activation and loss of tolerance are also features of mice with disrupted TGF-β signaling pathways [1,3]. In the absence of TGF-β, its activators [4], its receptors or signaling components, one of the tissues typically affected is the lung, evidence that TGF-β is essential for maintenance of normal lung physiology as well as the host response to injury, infections, or allergens.

Figure 1
Inflammatory lung pathology in TGF-β-deficient mice

TGF-β in lung pathogenesis

Within the mucosal immune system, the surface area of the lung is enormous, encompassing 100-150m2 or nearly the size of a volleyball court. The branching bronchial tree brings in oxygen, but also distributes environmental pollutants, antigens and infectious agents to ~300 million alveoli, the walls of which contain a dense capillary network and systemic access[5]. The respiratory epithelium not only functions as a barrier, but through mucociliary clearance, phagocytic cells, and antimicrobial peptides, orchestrates protective innate immunity and if need be, the transition into an adaptive immune response. Continuous bombardment by foreign agents requires a tightly controlled host response and one of the key immFunomodulatory agents is TGF-β.

Loss of control in response to environmental and genetic factors can engender pathogenesis, such as allergic asthma, characterized by recurrent inflammation, eosinophilia, airway hyperresponsiveness(AHR), mucus hypersecretion, and remodeling, all of which contribute to a decline in airway function. Approximately 300×106 people worldwide suffer with asthma, a heterogenous disease affecting all age groups, with increasing prevalence, especially in Western industrialized countries, a potential correlate of the hygiene hypothesis[6]. While multiple inflammatory cells and mediators participate in the pathophysiology of asthma, a biased T-helper(Th)2 lymphocyte response is considered crucial, together with a limited Th1 counterbalancing response, eosinophil, mast cell and basophil activation, IgE production, and more recently, evidence for participation by Th17 and possibly, Th9 cells (Fig. 2).

Figure 2
Model of airway inflammation with TGF-β intersecting points

A role for TGF-β in the wheezing and sneezing associated with allergic asthma stems from direct and circumstantial evidence. Not only have increased TGF-β and TGF-β signaling been detected in asthmatic airways (Fig. 3) and correlated with enhanced eosinophil infiltration, but an association with TGF-β polymorphism has also been reported [7]. Nonetheless, as often occurs with TGF-β, a disconnect appears to exist relevant to these genetic alterations and experimental model studies. Induced increases in TGF-β, whether by oral tolerance or retroviral delivery [8,9], ameliorated airway inflammation, whereas an exaggerated asthmatic phenotype occurred when TGF-β was reduced [10,11].

Figure 3
TGF-β in antigen-induced inflammation of the airways

Aberrant responses to allergens reflect insufficient control of Th2 effector cells and plasma cell immunoglobulin(Ig)E isotype-switch (Fig. 2). APC and multiple local factors polarize a Th2 response, along with recruitment via CCR3, CCR4 and CCR8 ligands. In turn, Th2-derived cytokines mediate and amplify airway inflammation and remodeling, and IL-5, in particular, provokes migration, differentiation and survival of eosinophils, an airway source of TGF-β. In sensitized individuals, allergen-specific IgE binds to mast cell FcεRI, and likely low affinity FcεR2(CD23) to engage signaling and release of histamine, proteoglycans, serine proteases, cytokines and lipid mediators, responsible for early phase reactions. TGF-β may suppress mast cell FcεRI, promote apoptosis, or induce inhibitor of DNA binding 2(Id2), a transcriptional regulator that negatively regulates B cell differentiation and dissuades IgE class switch recombination[12]. Increased specific IgG that captures allergen before it reaches effector cell IgE and a decreased IgE to IgG4 ratio have been associated with clinical improvement after immunotherapy, which usually coincides with induction of TGF-β and IL-10[13]. Although TGF-β inhibits T-cell proliferation and expression of lineage-associated transcription factors, T-bet and GATA-3, and thereby hobbles Th1 and Th2 differentiation [3], it also represents an essential switch factor in differentiation and maintenance of inducible CD4+CD25+ regulatory T cells (iTreg), Th17 and putative Th9 populations [14-17](Fig. 4).

Figure 4
TGF-β directs development of T helper populations

TGF-β supports differentiation of Th17 cells

Despite its ability to undermine Th2 responses, accumulating evidence pinpoints TGF-β in molding a population of pro-inflammatory IL-17-producing Th17 cells, which have a propensity to induce CXCL8/IL-8, recruit granulocytes, and enhance bronchial inflammation. Recently identified as a third lineage of T helper cells, distinct from classical Th1 and Th2, Th17 produce IL-17A and IL-17F that appear early, may integrate innate and adaptive immunity, but can serve as pathogenic effectors. The importance of TGF-β in Th17 commitment was first unraveled in mice in 2006 [15,18,19] and subsequently, in humans where TGF-β, combined with one or more cytokines (e.g. IL-6, IL-21, IL-23, IL-1β) directs the differentiation program of naïve T cells into Th17 [20-22](Fig. 4). In line with in vitro observations, overexpression of TGF-β1 in mouse T cells increased Th17 numbers [18]; conversely, mice deficient for TGF-β1 [15] or with attenuated T cell TGF-β signaling [23] had constrained Th17 development. RORgammat [24] and likely also RORalpha [25] represent key Th17 transcriptional factors, and their expression in naïve T cells is rapidly enhanced and sustained by TGF-β, together with IL-6. Under these conditions, another small subset that produces IL-10 plus IL-17 emerged [26] and, akin to conventional IL-10-producing Tr1, had protective functions. In an even more complex scenario, a subset of Th17 co-express IFNγ with IL-17, whereas committed Th17 deprived of TGF-β can apparently be re-programmed to T-bet/Stat4-dependent IFNγ-producing Th1 cells in the presence of IL-12 or, to a lesser extent by IL-23, extinguishing their RORγt/α and IL-17 production[27](Fig. 4). Whether this phenotype shift, contingent upon an altered balance between TGF-γ and IL-12/IL-23, occurs in asthmatic inflammation has not been explored, although little evidence for a Th1/IFNγ contribution exists. Nonetheless, these new findings highlight apparent Th17 plasticity, particularly during later stages of development, and remind us that there is much more to be deciphered regarding CD4+ T cell lineage commitment and function.

In an amplification arc, IL-17 stimulates bronchial fibroblasts, epithelial and smooth muscle cells to produce chemokines, inflammatory mediators(Fig. 2) and provokes epithelial mucus metaplasia, further contributing to airway pathology. Levels of IL-17 detected in asthmatic airways [28] seem to be linked to severity of disease and in the absence of infection where it serves to mobilize neutrophils and pulmonary defense, IL-17 can potentially be a bad actor. Transgenic mice overexpressing OVA-specific TCR genes in CD4+ T cells developed airway inflammation after OVA inhalation, dominated by neutrophils, cohabitants with Th1 and Th17 and their products, IFNγ and IL-17, in bronchoalveolar lavage(BAL). Although IFNγ-depletion exacerbated allergic responses, airway neutrophilia and hyperreactivity were dramatically alleviated in IL-17-deficient mice[29]. In support of this observation, Rag-2-deficient mice adoptively transferred with T-bet-deficient, but not wildtype CD4+ T cells, exhibited increased BAL granulocytes after OVA challenge, overridden by anti-IL-17 [30]. Likewise, Smad3 null mice, being defective in TGF-β-elicited Th17 development, exhibit reduced airway inflammatory cell infiltration and less severe tissue damage compared to wildtype when sensitized and challenged with a clinically relevant allergen, house dust mite(HDM)[31](Qian B. et al., in preparation).

Paradoxically, IL-17 has also been reported to be protective in certain Th2-mediated atopic models, where IL-17 neutralization exacerbated eosinophil recruitment and bronchial hyperreactivity, and exogenous IL-17 reduced symptoms [32]. Although the discrepancy remains unclear, this IL-17 inhibition was attributed to DC suppression and down-regulation of CCL17(TARC), eotaxin, and IL-5. Nonetheless, in humans, IL-17A and IL-17F are both TGF-β-dependent and often considered functionally interchangeable, yet an IL-17F-specific polymorphism has been linked to reduced incidence of asthma[33].

Th9, TGF-β and asthma

Based on rapidly evolving concepts of T cell plasticity, the involvement of TGF-β in phenotype shifting has become a moving target and the situation as it appears today will likely have morphed before the next review. Collectively, the current ensemble of data implicates TGF-β, in the context of changing cytokine cues, as the conductor of a T cell orchestra. In this regard, IL-9, upregulated in asthmatic lungs and a product of Th2 and eosinophils [34], has recently been tied to a T cell subset deviated from the Th2 lineage under the auspices of TGF-β and IL-4 [16,17](Fig. 4). Provisionally termed Th9, a putative additional helper T cell subset, these IL-9+ cells can be identified in HDM-induced experimental asthma(Fig. 3)(Qian B., et al., in preparation). Interestingly, HDM is a serine protease and serine protease inhibitors reportedly abolish eosinophil expression of IL-9 through antagonism of 7–transmembrane G protein-coupled protease activated receptors(PAR)2 [34]. IL-9, in turn, accentuates Th2 responses and differentiation of mast cells and hematopoietic progenitors. While clearly in the preliminary stages, elucidation of a link between TGF-β and IL-9 may reveal new avenues of intervention.

TGF-β regulates Treg development and function

With the assistance of TGF-β, the pro-inflammatory functions of Th17 and Th9 could spiral asthmatic pathogenesis out of control. Heroically, however, TGF-β may come to the rescue in the guise of a population of regulatory T cells. Naturally-occurring CD4+CD25+ Treg are derived from thymus with the early help of TGF-β [35] as a developmentally distinct subset of mature CD4+ T cells (5-10%) and, pre-programmed to perform suppressive functions, are critical in controlling immunity. Treg specifically express the transcription factor Foxp3, which masterfully regulates their development, function and survival. Mice devoid of functional Foxp3 develop a lethal autoimmune syndrome [36], rescuable by adoptive transfer of Treg.

In addition to thymically-originated Treg, activated naïve CD4+ T cells can acquire Foxp3 and differentiate into iTreg in the periphery, contingent upon TGF-β [1,14,18]. Blockade of TGF-β signaling in naïve T cells ablates conversion to iTreg, which manifests as T cell hyper-proliferation and overexuberant inflammation [3,37]. Recent significant findings suggest a reciprocal developmental relationship between Treg and Th17, two TGF-β-inducible CD4+ T cell subsets with opposing activities. Mediators, notably IL-2 and retinoic acid [38,39], which positively regulate Treg, suppress Th17 differentiation, while Th17-promoting IL-6 inhibits Treg [18]. In this same vein, their transcriptional factors, RORγt and Foxp3, can interact to block each other's function [40]. Similarly, Foxp3 and GATA-3 can antagonize one another, emphasizing the complex contextual regulation of T cell development.

Mechanistically, Treg-mediated immunomodulation is achieved by direct cell-to-cell interactions or release of regulatory cytokines, TGF-β and IL-10 [3,14,37]. Treg are pivotal in maintenance of tolerance to innocuous environmental antigens in health and despite increasing after allergen challenge (Fig. 3), may be functionally inadequate. Delivery of Foxp3+ Treg[14] to HDM-challenged mice suppressed inflammatory cell infiltration and collatoral damage, while depletion of Treg before HDM-challenge exacerbated airway responses [41]. Clinically, CD4+CD25+ Treg from asthmatic children are unable to inhibit either Th2 proliferative responses or cytokines, whereas parallel populations from non-asthmatics were functionally suppressive [42]. In this regard, a point mutation in the Foxp3 gene has recently been identified in an adult patient with both rhinitis and asthma[43]. Importantly, allergen immunotherapy or corticosteroid treatment, which bolster Foxp3-expressing T cells, attenuate asthmatic symptoms [44]. Intersecting resolution pathways managed via resolvins and lipoxins also dampen aspects of allergic inflammation including eosinophil activation [45] and may evoke release of TGF-β[46].

TGF-β, tissue repair and airway remodeling

Persistent inflammation and associated tissue damage trigger injury repair mechanisms, inevitably altering normal structural properties with resultant AHR and declining lung function. Within this milieu, TGF-β potentiates airway remodeling through a plethora of well-known functions in mediating wound healing and fibrosis [1], which exceed the scope of this review. Although elevated TGF-β in epithelial or submucosal cells have been correlated with basement membrane thickness and fibroblast numbers in asthmatic patients, evidence regarding support of TGF-β's contribution to experimental allergic airway remodeling is conflicting. Within the framework of TGF-β blockade or Smad3-deficiency, allergen(OVA)-induced remodeling is reduced [47,48,49]. Nonetheless, recent data indicate that HDM-induced asthmatic mice treated with neutralizing anti-TGF-β developed airway remodeling comparable to control mice, as did HDM-treated-Smad3 null mice[50], emphasizing, again, that the controlling factors in airway remodeling are not fully defined. This is not a trivial concern in that suggested efforts to manipulate TGF-β levels as a means to suppress allergic inflammation may negatively impact on fibrosis and airway remodeling. As asthma represents such a multifaceted and heterogeneous disease, it may be exceedingly difficult to target a single mediator and expect a miraculous reversal of pathology.


No longer can the case be made that TGF-β's major role in immunomodulation is strictly immunosuppressive. Rather, it has a constellation of activities that dominate from onset through resolution of innate and adaptive immune events. Conceivably, what is known today represents but the tip of the iceberg in our comprehension of the intertwined connections between TGF-β and a panoply of cells, cytokines, signaling molecules, and transcription factors which coalesce into an immune response appropriate for the inciting agent. From its early release by platelets, its ability to mobilize inflammatory cells directly and indirectly, and its unique orchestration of T cell lineage commitment, TGF-β clearly is fundamental to the nature and outcome of an evolving immune response. Tantamount to a master suppressor, TGF-β defines natural Treg development and iTreg conversion in the periphery. How a single molecule can exert such a diversity of activities is phenomenal, but clearly dependent on environmental cues. Basic discovery remains fundamental to understanding the underlying biology of inflammation and immunopathogenesis, and the unearthing of novel functions for TGF-β represented in the past several years may be but a harbinger of discoveries to come. Although it remains to be established whether targeting TGF-β, either to dampen or embellish selective activities, is appropriate, this approach has the potential to provide therapeutic strategies for multiple immune-based diseases and may help us all breathe a little easier.


The authors gratefully acknowledge the editorial assistance of Ms. Dara Stoney. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Dental and Craniofacial Research.


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*1. Wahl SM. Transforming growth factor-beta: innately bipolar. Curr Opin Immunol. 2007;19:55–62. [PubMed]The diverse roles of TGF-β in connection with cellular components of innate immunity, and the unique ability of TGF-β to direct lineage commitment of CD4+ T cells to both proinflammatory Th17 and anti-inflammatory Treg cells are highlighted, providing updated information regarding the bipolar nature of TGF-β.
2. Roberts AB, Anzano MA, Lamb LC, Smith JM, Sporn MB. New class of transforming growth factors potentiated by epidermal growth factor: isolation from non-neoplastic tissues. Proc Natl Acad Sci U S A. 1981;78:5339–5343. [PubMed]
*3. Li MO, Flavell RA. TGF-beta: a master of all T cell trades. Cell. 2008;134:392–404. [PMC free article] [PubMed]The authors reviewed TGF-β as a critical regulator in thymic T cell development as well as a crucial player in peripheral T cell homeostasis, tolerance to self antigens, and T cell differentiation.
4. Aluwihare P, Munger JS. What the lung has taught us about latent TGF-beta activation. Am J Respir Cell Mol Biol. 2008;39:499–502. [PMC free article] [PubMed]
5. Brain JD. Inhalation, deposition, and fate of insulin and other therapeutic proteins. Diabetes Technol Ther. 2007;9 1:S4–S15. [PubMed]
6. Rook GA. Review series on helminths, immune modulation and the hygiene hypothesis: the broader implications of the hygiene hypothesis. Immunology. 2009;126:3–11. [PubMed]
7. Ueda T, Niimi A, Matsumoto H, Takemura M, Yamaguchi M, Matsuoka H, Jinnai M, Chin K, Minakuchi M, Cheng L, et al. TGFB1 promoter polymorphism C-509T and pathophysiology of asthma. J Allergy Clin Immunol. 2008;121:659–664. [PubMed]
8. Haneda K, Sano K, Tamura G, Sato T, Habu S, Shirato K. TGF-beta induced by oral tolerance ameliorates experimental tracheal eosinophilia. J Immunol. 1997;159:4484–4490. [PubMed]
9. Hansen G, McIntire JJ, Yeung VP, Berry G, Thorbecke GJ, Chen L, DeKruyff RH, Umetsu DT. CD4(+) T helper cells engineered to produce latent TGF-beta1 reverse allergen-induced airway hyperreactivity and inflammation. J Clin Invest. 2000;105:61–70. [PMC free article] [PubMed]
10. Scherf W, Burdach S, Hansen G. Reduced expression of transforming growth factor beta 1 exacerbates pathology in an experimental asthma model. Eur J Immunol. 2005;35:198–206. [PubMed]
11. Schramm C, Herz U, Podlech J, Protschka M, Finotto S, Reddehase MJ, Kohler H, Galle PR, Lohse AW, Blessing M. TGF-beta regulates airway responses via T cells. J Immunol. 2003;170:1313–1319. [PubMed]
12. Sugai M, Gonda H, Kusunoki T, Katakai T, Yokota Y, Shimizu A. Essential role of Id2 in negative regulation of IgE class switching. Nat Immunol. 2003;4:25–30. [PubMed]
13. Akdis M, Akdis CA. Mechanisms of allergen-specific immunotherapy. J Allergy Clin Immunol. 2007;119:780–791. [PubMed]
14. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med. 2003;198:1875–1886. [PMC free article] [PubMed]
15. Mangan PR, Harrington LE, O'Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature. 2006;441:231–234. [PubMed]
**16. Veldhoen M, Uyttenhove C, van Snick J, Helmby H, Westendorf A, Buer J, Martin B, Wilhelm C, Stockinger B. Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol. 2008;9:1341–1346. [PubMed]The authors demonstrated the first evidence that TGF-β can reprogram Th2 cells to lose their characteristic profile and switch to IL-9 secretion or, in combination with IL-4, drive the differentiation of ‘TH-9’ cells directly.
**17. Dardalhon V, Awasthi A, Kwon H, Galileos G, Gao W, Sobel RA, Mitsdoerffer M, Strom TB, Elyaman W, Ho IC, et al. IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells. Nat Immunol. 2008;9:1347–1355. [PMC free article] [PubMed]Evidence that IL-4 inhibits generation of TGF-β-induced Foxp3+ Treg and instead induces a population of T helper cells that produce IL-9 and IL-10. The authors further showed that the IL-9+IL-10+ T cells lack suppressive function and constitute a distinct population of helper-effector T cells that promote tissue inflammation.
18. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441:235–238. [PubMed]
19. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006;24:179–189. [PubMed]
**20. Manel N, Unutmaz D, Littman DR. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol. 2008;9:641–649. [PMC free article] [PubMed]This article, together with [21] and [22] define an essential role for TGF-β in directing human Th17 lineage commitment. TGF-β, together with one or more pro-inflammatory cytokines was necessary and sufficient to induce IL-17 expression in naïve human CD4+ T cells and that RORγt serves as a differentiation factor, documenting that similar cytokine pathways are involved in Th17 cell development in mice and humans.
**21. Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupe P, Barillot E, Soumelis V. A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol. 2008;9:650–657. [PubMed]See annotation to [20].
**22. Yang L, Anderson DE, Baecher-Allan C, Hastings WD, Bettelli E, Oukka M, Kuchroo VK, Hafler DA. IL-21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature. 2008;454:350–352. [PMC free article] [PubMed]See annotation to [20].
23. Veldhoen M, Hocking RJ, Flavell RA, Stockinger B. Signals mediated by transforming growth factor-beta initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nat Immunol. 2006;7:1151–1156. [PubMed]
24. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126:1121–1133. [PubMed]
25. Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, Ma L, Shah B, Panopoulos AD, Schluns KS, et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity. 2008;28:29–39. [PMC free article] [PubMed]
*26. McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T, Cua DJ. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol. 2007;8:1390–1397. [PubMed]New evidence that stimulation with TGF-β and IL-6 induces IL-17 production in activated T cells together with IL-10, which abrogated the pathogenic function of Th17 cells in vivo. In contrast, stimulation with IL-23 promoted expression of IL-17 and proinflammatory chemokines but not IL-10. TGF-β and IL-6 may ‘drive’ initial lineage commitment but also ‘restrain’ the pathogenic potential of Th17 cells and that full acquisition of pathogenic function by effector Th17 cells is mediated by IL-23.
*27. Lee YK, Turner H, Maynard CL, Oliver JR, Chen D, Elson CO, Weaver CT. Late developmental plasticity in the T helper 17 lineage. Immunity. 2009;30:92–107. [PMC free article] [PubMed]Using an IL-17F reporter mouse, the authors showed that TGF-β was essential for maintenance of IL-17 expression. Stimulation of Th17 cells with IL-12 and/or IL-23 in the absence of TGF-β induced a rapid, STAT4- and T-bet-dependent transition marked by extinction of RORγt, RORα, IL-17A, and IL-17F and induction of IFN-γ. These findings support developmental plasticity of Th17 lineage and identify a mechanism for latent Th1-like responsiveness of Th17 cells.
28. Laan M, Linden A. The IL-17 family of cytokines--applications in respiratory medicine and allergology. Recent Pat Inflamm Allergy Drug Discov. 2008;2:82–91. [PubMed]
29. Nakae S, Suto H, Berry GJ, Galli SJ. Mast cell-derived TNF can promote Th17 cell-dependent neutrophil recruitment in ovalbumin-challenged OTII mice. Blood. 2007;109:3640–3648. [PubMed]
30. Fujiwara M, Hirose K, Kagami S, Takatori H, Wakashin H, Tamachi T, Watanabe N, Saito Y, Iwamoto I, Nakajima H. T-bet inhibits both TH2 cell-mediated eosinophil recruitment and TH17 cell-mediated neutrophil recruitment into the airways. J Allergy Clin Immunol. 2007;119:662–670. [PubMed]
31. Anthoni M, Wang G, Leino MS, Lauerma AI, Alenius HT, Wolff HJ. Smad3 -signalling and Th2 cytokines in normal mouse airways and in a mouse model of asthma. Int J Biol Sci. 2007;3:477–485. [PMC free article] [PubMed]
32. Schnyder-Candrian S, Togbe D, Couillin I, Mercier I, Brombacher F, Quesniaux V, Fossiez F, Ryffel B, Schnyder B. Interleukin-17 is a negative regulator of established allergic asthma. J Exp Med. 2006;203:2715–2725. [PMC free article] [PubMed]
33. Kawaguchi M, Takahashi D, Hizawa N, Suzuki S, Matsukura S, Kokubu F, Maeda Y, Fukui Y, Konno S, Huang SK, et al. IL-17F sequence variant (His161Arg) is associated with protection against asthma and antagonizes wild-type IL-17F activity. J Allergy Clin Immunol. 2006;117:795–801. [PubMed]
34. Fujisawa T, Katsumata H, Kato Y. House dust mite extract induces interleukin-9 expression in human eosinophils. Allergol Int. 2008;57:141–146. [PubMed]
**35. Liu Y, Zhang P, Li J, Kulkarni AB, Perruche S, Chen W. A critical function for TGF-beta signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat Immunol. 2008;9:632–640. [PubMed]TGF-β signaling is critical to thymic development of natural CD4+CD25+Foxp3+ Treg. Conditional deletion of TGF-βR1 in T cells blocked generation of CD4+CD25+Foxp3+ thymocytes at postnatal days 3-5, although beginning 1 week after birth, the same TGF-βRI mutant mice showed accelerated expansion of thymic CD4+CD25+Foxp3+ populations. The rapid recovery of Foxp3+ thymocytes was attributable to hyperresponsiveness to IL-2.
36. Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, Wilkinson JE, Galas D, Ziegler SF, Ramsdell F. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet. 2001;27:68–73. [PubMed]
37. Marie JC, Liggitt D, Rudensky AY. Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor. Immunity. 2006;25:441–454. [PubMed]
38. Laurence A, Tato CM, Davidson TS, Kanno Y, Chen Z, Yao Z, Blank RB, Meylan F, Siegel R, Hennighausen L, et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity. 2007;26:371–381. [PubMed]
*39. Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science. 2007;317:256–260. [PubMed]Retinoic acid was identified as a key regulator in TGF-β-dependent immune responses. Retinoic acid suppressed IL-6-driven induction of proinflammatory Th17 cells via reduction of RORγt and promoted anti-inflammatory FOXP3+ Treg differentiation. The reciprocal activity of RA might provide a self-correcting mechanism for TGF-β to regulate both pro- and anti-inflammatory immunity.
*40. Zhou L, Lopes JE, Chong MM, Ivanov II, Min R, Victora GD, Shen Y, Du J, Rubtsov YP, Rudensky AY, et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature. 2008;453:236–240. [PMC free article] [PubMed]TGF-β-induced Foxp3 interacts with RORγt and inhibits its function. Proinflammatory cytokines IL-6, IL-21 and IL-23 relieve Foxp3-mediated suppression of RORγt, thereby promoting Th17 cell commitment. These findings indicate that the decision of activated T cells to differentiate into either Th17 or Treg depends on the cytokine-regulated balance of RORγt and Foxp3.
41. Lewkowich IP, Herman NS, Schleifer KW, Dance MP, Chen BL, Dienger KM, Sproles AA, Shah JS, Kohl J, Belkaid Y, et al. CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function. J Exp Med. 2005;202:1549–1561. [PMC free article] [PubMed]
42. Hartl D, Koller B, Mehlhorn AT, Reinhardt D, Nicolai T, Schendel DJ, Griese M, Krauss-Etschmann S. Quantitative and functional impairment of pulmonary CD4+CD25hi regulatory T cells in pediatric asthma. J Allergy Clin Immunol. 2007;119:1258–1266. [PubMed]
43. Paik Y, Dahl M, Fang D, Calhoun K. Update: the role of FoxP3 in allergic disease. Curr Opin Otolaryngol Head Neck Surg. 2008;16:275–279. [PubMed]
44. Nouri-Aria KT, Durham SR. Regulatory T cells and allergic disease. Inflamm Allergy Drug Targets. 2008;7:237–252. [PubMed]
45. Starosta V, Pazdrak K, Boldogh I, Svider T, Kurosky A. Lipoxin A4 counterregulates GM-CSF signaling in eosinophilic granulocytes. J Immunol. 2008;181:8688–8699. [PMC free article] [PubMed]
46. Bannenberg GL, Chiang N, Ariel A, Arita M, Tjonahen E, Gotlinger KH, Hong S, Serhan CN. Molecular circuits of resolution: formation and actions of resolvins and protectins. J Immunol. 2005;174:4345–4355. [PubMed]
47. McMillan SJ, Xanthou G, Lloyd CM. Manipulation of allergen-induced airway remodeling by treatment with anti-TGF-beta antibody: effect on the Smad signaling pathway. J Immunol. 2005;174:5774–5780. [PubMed]
48. Le AV, Cho JY, Miller M, McElwain S, Golgotiu K, Broide DH. Inhibition of allergen-induced airway remodeling in Smad 3-deficient mice. J Immunol. 2007;178:7310–7316. [PubMed]
49. Alcorn JF, Rinaldi LM, Jaffe EF, van Loon M, Bates JH, Janssen-Heininger YM, Irvin CG. Transforming growth factor-beta1 suppresses airway hyperresponsiveness in allergic airway disease. Am J Respir Crit Care Med. 2007;176:974–982. [PMC free article] [PubMed]
50. Fattouh R, Midence NG, Arias K, Johnson JR, Walker TD, Goncharova S, Souza KP, Gregory RC, Jr, Lonning S, Gauldie J, et al. Transforming growth factor-beta regulates house dust mite-induced allergic airway inflammation but not airway remodeling. Am J Respir Crit Care Med. 2008;177:593–603. [PubMed]