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Inflammatory Bowel Diseases:
doi: 10.1097/MIB.0b013e31829ed7df
Basic Science Review Article

Keeping the Bowel Regular: The Emerging Role of Treg as a Therapeutic Target in Inflammatory Bowel Disease

Gibson, David J. MbChB, BAO*,†; Ryan, Elizabeth J. PhD*,†; Doherty, Glen A. Mb, PhD*,†

Free Access
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Author Information

*Centre for Colorectal Disease, St. Vincent’s University Hospital, Dublin, Ireland; and

School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland.

Reprints: David J Gibson, MbChB, BAO, Centre for Colorectal Disease, St. Vincent’s University Hospital, Elm Park, Dublin, Ireland (e-mail: gibsond@tcd.ie).

The authors have no conflicts of interest to disclose.

Received May 15, 2013

Accepted June 06, 2013

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Abstract

The understanding of the intricate mechanisms by which gut immune cells interact with each other and the intestinal flora is constantly developing. The mucosal immune system must retain the ability to mount a prompt response to intestinal pathogens while maintaining tolerance for commensal organisms. Effector T lymphocytes drive inflammation, whereas their actions are counteracted by populations of regulatory T cells (Treg), which act as an endogenous suppressor of mucosal inflammation. There is growing evidence that a loss of this delicate counterbalance is important in the etiology of inflammatory bowel disease (IBD). Here, we review studies highlighting alterations in Treg in the pathogenesis of IBD. Observations of dynamic changes in Treg activity with successful IBD treatment have highlighted their functional importance and potential to also serve as a biomarker of disease activity and to predict response to therapy. Furthermore, we explore the potential for adoptive transfer of Treg as part of IBD treatment.

Inflammatory bowel diseases (IBDs) are a group of chronic, relapsing inflammatory disorders of the intestine with 2 major subgroups: Crohn’s disease (CD) and ulcerative colitis (UC). Although the pathogenesis of IBD is not fully understood, there is an emerging consensus that IBD results from a disrupted balance between the mucosal immune system and the gut microflora. The intestinal flora is altered in IBD patients, and this so-called “dysbiosis” may represent both cause and effect. Mucosal barrier disruption facilitates recruitment and activation of a potent proinflammatory immune response, which fails to resolve and results in persistent mucosal inflammation.1,2 The failure of resolution points to potential defects in endogenous mechanisms in the intestinal immune system, which regulate and suppress intestinal inflammation.

In this review, we aim to clarify recent advances in this field, specifically in relation to human regulatory T cells (Treg), a vital player in the maintenance of immune homeostasis in the gut. We will examine the evidence suggesting that Treg are altered in patients with IBD. In addition, we will highlight the observations of numerical and functional alterations in Treg associated with changes in disease activity and treatment response, notably response to antitumor necrosis factor (TNF) α therapy. Finally, we will discuss the potential use of Treg as part of IBD therapeutics, in particular highlighting recent human studies where Treg transfer successfully suppressed inflammation in IBD, representing proof of concept.

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ROLE OF Treg IN THE HUMAN INTESTINE

Treg constitute 1% to 5% of peripheral blood T cells in healthy adults3 and play a key role in suppression of inappropriate immune responses. In the lamina propria (LP), a range of luminal antigens can generate proinflammatory responses and Treg play an important role in preventing development of pathological immune-mediated responses.4,5 They exert their homeostatic influence by applying a dominant negative regulation on other immune cells, such as T effectors. Treg can mediate contact-dependent suppression, i.e., via molecules such as cytotoxic T-lymphocyte antigen 46 or by production of cytokines such as interleukin (IL)-10 and transforming growth factor (TGF) β. Treg both produce and respond to TGF-β, an anti-inflammatory cytokine that plays an important role in the maintenance of immune homeostasis.7 In addition, Treg can also generate anti-inflammatory signals via other mechanisms, such as through the action of cell surface ecto-enzymes such as CD39, which neutralize the proinflammatory effects of extracellular nucleotides such as ATP.8 Infusion of Treg is capable of curing experimental colitis in animal models,9,10 and this has prompted a rapid expansion in research in this area. However, much remains to be discovered about the phenotype, function, and plasticity of human Treg before we can translate much of this knowledge to the clinic.

Naive T cells can differentiate into either Treg or T cells of the effector lineage,11 as depicted in Figure 1. The balance of differentiation is critical in maintenance of intestinal homeostasis. Tipping the balance may allow effector T cells to proliferate in an unregulated fashion, promoting the development of chronic intestinal inflammation. In the setting of IBD, activated mucosal T lymphocytes are increased in number.12 Therefore, continuous Treg differentiation and trafficking in the gut is required to dampen immune reactions to commensal bacteria and dietary antigens.13

FIGURE 1.
FIGURE 1.
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Treg POPULATIONS

Broadly speaking, Treg can be divided into subtypes: natural or adaptive. Natural regulatory T cell (nTreg) are CD4+CD25+ and originate in the thymus. Adaptive regulatory T cells (iTreg) are CD4+ and acquire CD25 positivity outside the thymus, typically in the setting of inflammation.13 A third, less well-defined population of Treg also exists, which are termed type 1 regulatory (Tr1) cells. Tr1 cells do not express FoxP3. They are induced peripherally in the presence of IL-10 both in vitro and in vivo,14 but there are little data on their role in intestinal immunity and so our discussion will focus on the first 2 categories of cells.

Treg were initially defined by surface expression of CD4+CD25+.15 However, as CD25, the alpha-chain of the IL-2 receptor, is commonly induced on T-cell activation,16 additional cell markers are clearly needed to define this population. In most studies, Treg are now identified as CD4+ T cells with a combination of high levels of CD25 and low levels of CD127 expression (CD4+CD25brightCD127low). Other surface markers such as CD39 have also been recognized as being associated with the Treg phenotype. However, it is the expression of the transcription factor, Fox P3, which is crucial to the regulatory activity of Treg17,18 and in defining the Treg populations.

CD4+FoxP3+ Treg are crucial to intestinal homeostasis,19 so much so that they have been described as “master regulators” of immune homeostasis.20,21

The functional importance of FoxP3 is underlined by the observation that in humans, mutations in FoxP3 causes development of immune deregulation polyendocrinopathy enteropathy and X-linked syndrome.22 Immune deregulation polyendocrinopathy enteropathy and X-linked syndrome is characterized by severe inflammation. The most frequently affected organ in this syndrome is the intestine, which exemplifies the important of this transcription factor in gut homeostasis.

Natural Tregs are generated in the thymus under the control of MHC class II-dependent T-cell receptors.23 Differentiation of adaptive Treg occurs in more varied circumstances than that of natural Treg,24 and the different microenvironments in which adaptive Treg develop in vivo is still not fully understood. The distinct signaling pathways controlling thymic (nTreg) versus peripheral (iTreg) induction of Treg has been investigated. Although thymic differentiation can occur in the absence of TGF β, TGFβ seems crucial for the activation of the suppressive capacity of Treg.25 Induction of FoxP3 seems dependent on TGFβ signaling, both in vivo and in vitro. The intestine is known to be rich in TGF β, thus facilitating local Treg differentiation.26 Gut-associated lymphoid tissue provides an environment for de novo generation of adaptive Treg, independent of thymic control, in response to activation by microbial antigens.27 Indeed, the intestinal microbiota promotes intestinal Treg-cell development, as Treg cell accumulation in the colon is reduced in germ-free mice.28

Activation of the innate immune system by microbiota occurs via a myriad of pattern-recognition receptors such as the Toll-like receptors (TLR) and NOD-like receptors.29

In mice, a deficiency in TLR-9 results in increased frequency of FoxP3+Treg,30 whereas deficiencies in TLR-2 result in a reduction of FoxP3+ Tregs.31

Both nTreg and iTreg secrete the anti-inflammatory cytokine IL-10. Although under steady-state conditions in the spleen and mesenteric lymph nodes Treg produce very little IL-10, they are the main CD4+ T-cell population producing IL-10 in the colonic LP.32 Recent studies have highlighted the importance of the anti-inflammatory properties of IL-10 in the human intestine. Loss of function in IL-10 and the IL-10 receptor are associated with early onset IBD with an aggressive phenotype.33 Furthermore, allogeneic hematopoietic stem cell tranplants has been used to good effect in IL-10- and IL-10 receptor-deficient patients.34,35 However, therapy based on recombinant IL-10 does not seem to provide any benefit for the treatment of active CD.36 Understanding the role of IL-10 in the regulation of inflammation in the human intestine may help us to better exploit its anti-inflammatory properties clinically.

As mentioned, a fine balance exists between Treg and effector T cells in the healthy state. One arm of the effector response is the Th17 pathway, which has an antagonistic relationship with Treg. The same naive T cell pool that generates Treg is also capable of producing Th17 effector T cells,37 and this is coordinated by TGF-β. Reduced frequency of Treg in IBD is associated with high levels of Th17.38 In the presence of infection or inflammation, IL-6 suppresses Treg production with the activation of a predominantly Th17 mediated proinflammatory response.39 IL-1β is also required for the differentiation of Th17 induction.40 In a manner similar to TGF-β, IL-6 is an important signaling protein, and in its presence, as found in active inflammation, Treg induction is blocked.41

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TReg FUNCTION: LESSONS FROM MOUSE MODELS OF IBD

The role of Treg has been well studied in a range of murine models of IBD, and the results of these are summarized in Table 1. From initial studies, it became apparent that FoxP3 is integral to intestinal homeostasis.42,43 Subsequent studies have highlighted the mechanism by which naive T cells differentiate into Treg,20,26 the key role of Treg production of IL-10,10,32 and the mechanisms by which Treg suppress effector T cells44,45 and exert their anti-inflammatory role. The Wiskott–Aldrich syndrome protein is required for Treg function, and Wiskott–Aldrich syndrome protein knockout (WKO) nTreg lack the suppressive ability.46 Numbers of Treg were found to be reduced in colitic mice compared with controls,47 and further research provided an exciting potential avenue for IBD treatment, with the cure of colitis by the transfer of Treg.9 In the majority of these studies, Treg were defined by CD4+CD25+FoxP3+.

TABLE 1
TABLE 1
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Treg LEVELS AND FUNCTION IN HUMAN IBD

The evidence in relation to the precise role of Tregs in IBD in humans is somewhat conflicting.

The key clinical studies that have evaluated the phenotype/function of Treg in both peripheral blood and the intestine of IBD patients are summarized in Table 2 and highlight the somewhat inconsistent findings. Although numerous trials have supported the hypothesis of reduced Treg in the active state,48–51 contradictory findings have also been found.52–55 In a comparison of patients with both UCand CD, versus control patients, Maul et al found that, in peripheral blood, increased Treg activity is found in remission, whereas, at mucosal level, higher levels of FoxP3 were found in inflamed mucosa. Contrasting to this, Saruta et al found increased Treg activity in active CD versus controls, both peripherally and in intestinal mucosa.

TABLE 2
TABLE 2
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Although some of these conflicting observations may be explained by the use of limited panels of Treg markers in some studies, this alone is not sufficient to explain the somewhat discordant findings. Transient FoxP3 expression may be observed on activation of effector T cells, making reliance on FoxP3 expression alone unreliable.56 In addition, it is now clear that the concept of strict reciprocity between Treg and Th17 cell phenotypes is not valid. T-cell populations not only positive for FoxP3 but also producing IL-17 have recently been observed in the intestinal LP of IBD patients. Interestingly, despite producing IL-17, these cells seem to retain a suppressive phenotype.57

A correlation between disease activity and Treg concentration has been described. In the setting of UC, Holmen et al58 found a positive correlation between Treg frequency and disease activity. This further confuses matters but may suggest that, although increased in the active state, the function of Treg is impaired, and as such, T-effector cells are inadequately suppressed. In other autoimmune conditions such as rheumatoid arthritis (RA), there is evidence that Treg function is compromised in active disease,59 and similarly, in the setting of systemic lupus erythematous, Treg function is deficient.60

No definite evidence of a functional defect in human Treg has been identified to date in IBD studies. It has been suggested that, rather than a primary defect in Treg activity, IBD may be more associated with an effector cell phenotype that is resistant to Treg suppression. Colitogenic T cells obtained from patients with IBD have been described, which seem resistant to the anti-inflammatory effect of TGF-β.13 Augmented activity of the signaling molecule Smad7, a negative regulator of TGF-β signaling has been proposed as a mechanism, and antisense oligonucleotides, which would inhibit Smad7 activity, are in early clinical trials in IBD.61 However, the absence of spontaneous colitis in Smad7 transgenic mice, which overexpress this molecule, has caused some to question the importance of this pathway.62 It is also clear that effective treatment of IBD is associated with dynamic changes in human Treg and that Treg resistance has not proved a barrier to the effective use of adoptive transfer of Treg as an IBD therapy.

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ROLE OF TNF IN IBD/EFFECTS OF ANTI-TNFα THERAPY ON Treg

Anti-TNFα therapy, administered either intravenously or subcutaneously, is now well established as effective therapy for IBD.

Initially, animal models showed a role for TNFα in chronic intestinal inflammation,63 and subsequently, TNFα was found to have an important role in pathogenesis of CD64 and UC.65 Neutralization of TNFα results in the downregulation of proinflammatory cytokines, including IL-17, IL-23, and IL-666 with potential effects on T-cell differentiation in inflamed tissue.

However, approximately one-third of patients with IBD do not respond to anti-TNF treatment, whereas others lose responsiveness or become intolerant.67 The precise mechanisms underlying the action of anti-TNFα treatment, and the reasons for nonresponse have not been elucidated in full. Paradoxically, new onset IBD has been reported in some patients treated with anti-TNF agents for other inflammatory conditions.68,69 Given the fact that some anti-TNF therapies, such as etanercept, are ineffective in CD,70 this further illustrates the complex mechanism by which anti-TNF treatments exert their effect.

It is possible that the inflammation in patients who do not respond to anti-TNFα treatment is driven independently of TNFα. As can be seen in Figure 1, other proinflammatory cytokines, independent of TNFα pathways, such as IL-6 and IL-17, play an important role in the inflammatory cascade, further supported by numerous clinical trials in these areas.71–73

In other autoimmune conditions such as RA, anti-TNF treatment has been shown to have a restorative effect on Treg59 and further studies in RA have shown that anti-TNF treatment increases FoxP3 expression, thereby augmenting the Treg suppressive function.74,75 The effects of anti-TNF therapy on Treg also provide contrasting results when assessed in different IBD patient cohorts; the results of studies to date are summarized in Table 3.

TABLE 3
TABLE 3
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One emerging theory is that there is increased apoptosis of Treg in patients with active IBD. In patients who respond to treatment, anti-TNF therapies seem to reduce this apoptosis, thereby increasing the ratio of Treg:T effectors,48 which may be important in the therapeutic efficacy of these agents.

Anti-TNF antibodies also seem to induce apoptosis of mucosal CD4+ cells in inflamed mucosa.76 In contrast, minimal apoptosis takes place in peripheral blood. This suggests that these agents are acting selectively on membrane-bound TNF-bearing pathogenic intestinal lymphocytes.77 However, other authors have produced data to contradict this theory, showing that anti-TNF therapy caused increased levels of Treg in peripheral blood, with a reciprocal decrease in intestinal mucosa.78

There does appear to be stronger evidence to support the theory of anti-TNF treatment increasing Treg function.49,50,79 However, given the fact that numerous articles have contradicted this evidence,51,80–83 we are left with more questions than answers.

The exact markers that exclusively define Treg in humans remain an area of active debate. CD4+CD25+FoxP3+ cells may define a significant majority, but, as already described, Tr1 cells do not express FoxP3.

The varying ways in which different studies have defined Treg populations, as illustrated in Table 2, may help explain some of the contrasting observations. Markers such as cytotoxic T-lymphocyte antigen 4,84 Ki67,85 and CD127 negativity confer further purity.86 Other cell surface markers such as CD39 and CD73 may be useful in identifying Treg, particularly those subpopulations with a propensity to Th17 differentiation.87,88 As described by Collison and Vignali,89 Treg functional suppression assays appear crucial to classify this T-cell population and future studies need to focus on isolation and characterization of human Treg populations in IBD patients.

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FUTURE DIRECTIONS—Treg AS IBD THERAPY

Given the sustained interest in the role of Treg in IBD pathogenesis, efforts persist into how Treg can be incorporated into a viable form of therapy for humans with IBD.

The transition of knowledge from animal to human models is always challenging. What may be effective treatment in animal models may have little effect in humans, and the limitations of murine models of IBD compared with humans are clear.90

The challenges of Treg transfer therapy are manifold. If Treg are to be infused, it will be necessary to select a cell population, which is a pure pool of Treg. Avoidance of contamination with effector T cells is critical. In addition, it is not known whether in vitro T cells infused in vivo will retain their regulatory capacity or differentiate into effector cells. If the latter occurs, there could be an unwanted exacerbation of the autoimmune process. This is supported by studies showing differentiation of Treg at the site of inflammation into T effectors of the Th1 and Th17 lineage.91,92

Ongoing studies are identifying further cell surface molecules to help differentiate T-cell subpopulations and, therefore, offer the potential for a more pure collection.93 There is the potential that harvested Treg could undergo ex vivo reconditioning with agents such as rapomycin and retinoic acid, with a view to potentiating their suppressive function.94 Emerging biologic treatments in IBD, such as ustekinumab, have targeted ILs such as IL-23, involved in the promotion of the Th17 effector pathway,95,96 could be used in conjunction with Treg transfer to maximize clinical effectiveness.

One unanswered question relates to the patient-to-patient variability in the intestinal microbiota, which has a critical role in the evolution of IBD.

With each patient comes a different microenvironment. It is known that some commensals specifically promote FoxP3 Treg,28,97 whereas others have shown that commensal bacteria exploit the TLR pathway to actively suppress immunity.98

How in vitro T cells will adapt to contrasting gut microenvironments in vivo is unknown. Manipulation of the intestinal flora may provide an additional avenue to potentiating the effectiveness of adoptive transfer Treg therapy.

Recent clinical data offer significant grounds for optimism in this field as the CATS1 study, performed by Desreumaux et al,99 provides evidence of the efficacy of Treg treatment in the setting of refractory CD. In this open-labeled study, autologous antigen-specific Treg were collected, purified ex vivo, and then infused at varying doses. Results were promising, and with 1 concentration of infusion, there was a 75% response rate. Admittedly, study numbers were small, but this landmark study may pave the way for the introduction of Treg-based treatment in IBD.

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CONCLUSIONS

Although many questions remain unanswered, it is clear that Treg play a critical role in gut homeostasis and that numerical and functional alterations in Treg are observed in humans with IBD, which seems important in disease pathogenesis. With improved characterization of the full panel of Treg markers in humans, a better understanding of the role of Treg is emerging. Changes in Treg that are observed in conjunction with successful use of anti-TNF agents may explain some of their beneficial effects on IBD disease activity. New molecular approaches to promote the regulatory pathway in T cells, whereas dampening the effector pathway, have considerable promise as a part of future anti-inflammatory strategies. Recent clinical data provide proof of concept that adoptive transfer of Treg has potential as an effective disease therapy for IBD. Further studies in this area should be prioritized.

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REFERENCES

1. Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med. 2011; 365:1713–1725.

2. Maloy KJ, Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. 2011; 474:298–306.

3. Tang Q, Bluestone JA. The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat Immunol. 2008; 9:239–244.

4. Bluestone JA, Tang Q. How do CD4+CD25+ regulatory T cells control autoimmunity? Curr Opin Immunol. 2005; 17:638–642.

5. Hadis U, Wahl B, Sculz O, et al. Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. Immunity. 2011; 34:237–246.

6. Li MO, Flavell RA. Contextual regulation of inflammation: a duet by transforming growth factor-beta and interleukin-10. Immunity. 2008; 28:468–476.

7. Fantini MC, Rizzo A, Fina D, et al. Smad7 controls resistance of colitogenic T cells to regulatory T cell-mediated suppression. Gastroenterology. 2009; 136:1308–1316;

e1301–1303.


8. Deaglio S, Dwyer KM, Gao W, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med. 2007; 204:1257–1265.

9. Mottet C, Uhlig HH, Powrie H. Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J Immunol. 2003; 170:3939–3943.

10. Veltkamp C, Ruhwald R, Giesem T, et al. CD4+CD25+ cell depletion from the normal CD4+ T cell pool prevents tolerance toward the intestinal flora and leads to chronic colitis in immunodeficient mice. Inflamm Bowel Dis. 2006; 12:437–446.

11. Monteleone G, Pallone F, MacDonald TT. Interleukin-21: a critical regulator of the balance between effector and regulatory T-cell responses. Trends Immunol. 2008; 29:290–294.

12. Sturm A, Mohr S, Fiocchi C. Critical role of caspases in the regulation of apoptosis and proliferation of mucosal T cells. Gastroenterology. 2002; 122:1334–1345.

13. Curotto de Lafaille MA, Lafaille JJ. Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity. 2009; 30:626–635.

14. Roncarolo MG, Gregori S, Battaglia, et al. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev. 2006; 212:28–50.

15. Sakaguchi S, Sakaguchi N, Asano M, et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995; 155:1151–1164.

16. Allan SE, Crome SQ, Crellin N, et al. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol. 2007; 19:345–354.

17. Zheng Y, Rudensky AY. Foxp3 in control of the regulatory T cell lineage. Nat Immunol. 2007; 8:457–462.

18. Hori S, Nomura T, Sakaguchi S, et al. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003; 299:1057–1061.

19. Powrie F, Read S, Mottet C, et al. Control of immune pathology by regulatory T cells. Novartis Found Symp. 2003; 252:92–98;

discussion 98–105, 106–114


20. Fontenot JD, Gavin MA, Rudensky, et al. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003; 4:330–336.

21. Khattri R, Cox T, Yasayko, et al. An essential role for Scurfin in CD4+CD25+ T regulatory cells.2003; 337–342.

22. Bennett CL, Christie J, Ramsdell F, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001; 27:20–21.

23. Apostolou I, Sarukhan A, Klein L, et al. Origin of regulatory T cells with known specificity for antigen. Nat Immunol. 2002; 3:756–763.

24. Josefowicz SZ, Rudensky A. Control of regulatory T cell lineage commitment and maintenance. Immunity. 2009; 30:616–625.

25. Selvaraj RK, Geiger TL. A kinetic and dynamic analysis of Foxp3 induced in T cells by TGF-beta. J Immunol. 2007; 178:7667–7677.

26. Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med. 2003; 198:1875–1886.

27. Sun CM, Hall JA, Blank RB, et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med. 2007; 204:1775–1785.

28. Atarashi K, Tanoue T, Shima T, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science. 2011; 331:337–341.

29. Lavelle EC, Murphy C, O'Neill LA, et al. The role of TLRs, NLRs, and RLRs in mucosal innate immunity and homeostasis. Mucosal Immunol. 2010; 3:17–28.

30. Hall JA, Bouladoux N, Sun CM, et al. Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses. Immunity. 2008; 29:637–649.

31. Sutmuller RP, den Brok MH, Kramer M, et al. Toll-like receptor 2 controls expansion and function of regulatory T cells. J Clin Invest. 2006; 116:485–494.

32. Uhlig HH, Coombes J, Mottet C, et al. Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis. J Immunol. 2006; 177:5852–5860.

33. Glocker EO, Kotlarz D, Boztug H, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009; 361:2033–2045.

34. Kotlarz D, Beier R, Murugan D, et al. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology. 2012; 143:347–355.

35. Engelhardt KR, Shah N, Faizura-Yeop I, et al. Clinical outcome in IL-10- and IL-10 receptor-deficient patients with or without hematopoietic stem cell transplantation. J Allergy Clin Immunol. 2013; 131:825–830.

36. Buruiana FE, Sola I, Alonso-Coello P. Recombinant human interleukin 10 for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2010; :CD005109

37. Veldhoen M, Hocking RJ, Atkins CJ, et al. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006; 24:179–189.

38. Eastaff-Leung N, Mabarrack N, Barbour A, et al. Foxp3+ regulatory T cells, Th17 effector cells, and cytokine environment in inflammatory bowel disease. J Clin Immunol. 2010; 30:80–89.

39. Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006; 441:235–238.

40. Mills KH, Dungan LS, Jones SA, et al. The role of inflammasome-derived IL-1 in driving IL-17 responses. J Leukoc Biol. 2013; 93:489–497.

41. Dominitzki S, Fantini MC, Neufert C, et al. Cutting edge: trans-signaling via the soluble IL-6R abrogates the induction of FoxP3 in naive CD4+CD25 T cells. J Immunol. 2007; 179:2041–2045.

42. Brunkow ME, Jeffery EW, Hjerrild KA, et al. 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.

43. Makita S, Kanai T, Nemoto Y, et al. Intestinal lamina propria retaining CD4+CD25+ regulatory T cells is a suppressive site of intestinal inflammation. J Immunol. 2007; 178:4937–4946.

44. Pandiyan P, Zheng L, Ishihara S, et al. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat Immunol. 2007; 8:1353–1362.

45. Ogino H, Nakamura K, Ihara E, et al. CD4+CD25+ regulatory T cells suppress Th17-responses in an experimental colitis model. Dig Dis Sci. 2011; 56:376–386.

46. Maillard MH, Cotta-de-Almeida V, Takeshima F, et al. The Wiskott-Aldrich syndrome protein is required for the function of CD4(+)CD25(+)Foxp3(+) regulatory T cells. J Exp Med. 2007; 204:381–391.

47. Ishimaru N, Yamada A, Kohashi M, et al. Development of inflammatory bowel disease in Long-Evans Cinnamon rats based on CD4+CD25+Foxp3+ regulatory T cell dysfunction. J Immunol. 2008; 180:6997–7008.

48. Veltkamp C, Anstaett M, Wahl K, et al. Apoptosis of regulatory T lymphocytes is increased in chronic inflammatory bowel disease and reversed by anti-TNF alpha treatment. Gut. 2011; 60:1345–1353.

49. Boschetti G, Nancey S, Sardi F, et al. Therapy with anti-TNF alpha antibody enhances number and function of Foxp3(+) regulatory T cells in inflammatory bowel diseases. Inflamm Bowel Dis. 2011; 17:160–170.

50. Ricciardelli I, Lindley KJ, Londei M, et al. Anti tumour necrosis-alpha therapy increases the number of FOXP3 regulatory T cells in children affected by Crohn’s disease. Immunology. 2008; 125:178–183.

51. Dige A, Hvas CL, Deleuran B, et al. Adalimumab treatment in Crohn’s disease does not induce early changes in regulatory T cells. Scand J Gastroenterol. 2011; 46:1206–1214.

52. Maul J, Loddenkemper C, Mundt P, et al. Peripheral and intestinal regulatory CD4+ CD25 (high) T cells in inflammatory bowel disease. Gastroenterology. 2005; 128:1868–1878.

53. Saruta M, Yu QT, Fleshner PR, et al. Characterization of FOXP3+CD4+ regulatory T cells in Crohn’s disease. Clin Immunol. 2007; 125:281–290.

54. Yu QT, Saruta M, Avanesyan A, et al. Expression and functional characterization of FOXP3+ CD4+ regulatory T cells in ulcerative colitis. Inflamm Bowel Dis. 2007; 13:191–199.

55. Reikvam DH, Perminow G, Lyckander LG, et al. Increase of regulatory T cells in ileal mucosa of untreated pediatric Crohn’s disease patients. Scand J Gastroenterol. 2011; 46:550–560.

56. Kmieciak M, Gowda M, Graham L, et al. Human T cells express CD25 and Foxp3 upon activation and exhibit effector/memory phenotypes without any regulatory/suppressor function. J Transl Med. 2009; 7:89

57. Hovhannisyan Z, Treatman J, Littman DR, et al. Characterization of interleukin-17-producing regulatory T cells in inflamed intestinal mucosa from patients with inflammatory bowel diseases. Gastroenterology. 2011; 140:957–965.

58. Holmen N, Lundgren A, Lundin S, et al. Functional CD4+CD25high regulatory T cells are enriched in the colonic mucosa of patients with active ulcerative colitis and increase with disease activity. Inflamm Bowel Dis. 2006; 12:447–456.

59. Ehrenstein MR, Evans JG, Singh A, et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy. J Exp Med. 2004; 200:277–285.

60. Valencia X, Yarboro C, Illei G, et al. Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol. 2007; 178:2579–2588.

61. Monteleone G, Fantini MC, Onali S, et al. Phase I clinical trial of Smad7 knockdown using antisense oligonucleotide in patients with active Crohn’s disease. Mol Ther. 2012; 20:870–876.

62. Nakao A, Miike S, Hatano M, et al. Blockade of transforming growth factor beta/Smad signaling in T cells by overexpression of Smad7 enhances antigen-induced airway inflammation and airway reactivity. J Exp Med. 2000; 192:151–158.

63. Kaser A, Zeissig S, Blumberg RS, et al. Inflammatory bowel disease. Annu Rev Immunol. 2010; 28:573–621.

64. Plevy SE, Landers CJ, Prehn J, et al. A role for TNF-alpha and mucosal T helper-1 cytokines in the pathogenesis of Crohn’s disease. J Immunol. 1997; 159:6276–6282.

65. Murch SH, Braegger CP, Walker-Smith JA, et al. Location of tumour necrosis factor alpha by immunohistochemistry in chronic inflammatory bowel disease. Gut. 1993; 34:1705–1709.

66. Liu Z, Jiu J, Liu S, et al. Blockage of tumor necrosis factor prevents intestinal mucosal inflammation through down-regulation of interleukin-23 secretion. J Autoimmun. 2007; 29:187–194.

67. Melmed GY, Targan SR. Future biologic targets for IBD: potentials and pitfalls. Nat Rev Gastroenterol Hepatol. 2010; 7:110–117.

68. van Dijken TD, Vastert SJ, Gerloni VM, et al. Development of inflammatory bowel disease in patients with juvenile idiopathic arthritis treated with etanercept. J Rheumatol. 2011; 38:1441–1446.

69. Toussirot É, Houvenagel É, Goëb V, et al. Development of inflammatory bowel disease during anti-TNF-alpha therapy for inflammatory rheumatic disease. A nationwide series. Joint Bone Spine. 2012; 79:457–463.

70. Sandborn WJ, Hanauer SB, Katz S, et al. Etanercept for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology. 2001; 121:1088–1094.

71. Yen D, Cheung J, Scheerens H, et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest. 2006; 116:1310–1316.

72. Fina D, Sarra M, Fantini MC, et al. Regulation of gut inflammation and th17 cell response by interleukin-21. Gastroenterology. 2008; 134:1038–1048.

73. Fujino S, Andoh A, Bamba S, et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut. 2003; 52:65–70.

74. Nadkarni S, Mauri C, Ehrenstein MR. Anti-TNF-alpha therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-beta. J Exp Med. 2007; 204:33–39.

75. Ehrenstein MR, Evans JG, Singh A, et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy. J Exp Med. 2004; 200:277–285.

76. Atreya R, Zimmer M, Bartsch B, et al. Antibodies against tumor necrosis factor (TNF) induce T-cell apoptosis in patients with inflammatory bowel diseases via TNF receptor 2 and intestinal CD14(+) macrophages. Gastroenterology. 2011; 141:2026–2038.

77. Mitoma H, Horiuchi T, Hatta N, et al. Infliximab induces potent anti-inflammatory responses by outside-to-inside signals through transmembrane TNF-alpha. Gastroenterology. 2005; 128:376–392.

78. Li Z, Arijs I, De Hertogh G, et al. Reciprocal changes of Foxp3 expression in blood and intestinal mucosa in IBD patients responding to infliximab. Inflamm Bowel Dis. 2010; 16:1299–1310.

79. Di Sabatino A, Biancheri P, Piconese S, et al. Peripheral regulatory T cells and serum transforming growth factor-beta: relationship with clinical response to infliximab in Crohn’s disease. Inflamm Bowel Dis. 2010; 16:1891–1897.

80. Hvas CL, Kelsen J, Agnholt J, et al. Discrete changes in circulating regulatory T cells during infliximab treatment of Crohn’s disease. Autoimmunity. 2010; 43:325–333.

81. Grundstrom J, Linton L, Thunberg S, et al. Altered immunoregulatory profile during anti-tumour necrosis factor treatment of patients with inflammatory bowel disease. Clin Exp Immunol. 2012; 169:137–147.

82. Rismo R, Olsen T, Cui G, et al. Mucosal cytokine gene expression profiles as biomarkers of response to infliximab in ulcerative colitis. Scand J Gastroenterol. 2012; 47:538–547.

83. Kelsen J, Agnholt J, Hoffmann HJ, et al. FoxP3(+)CD4(+)CD25(+) T cells with regulatory properties can be cultured from colonic mucosa of patients with Crohn’s disease. Clin Exp Immunol. 2005; 141:549–557.

84. Wing K, Onishi Y, Prieto-Martin P, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008; 322:271–275.

85. Booth NJ, McQuaid AJ, Sobande T, et al. Different proliferative potential and migratory characteristics of human CD4+ regulatory T cells that express either CD45RA or CD45RO. J Immunol. 2010; 184:4317–4326.

86. Yu N, Li X, Song W, et al. CD4(+)CD25 (+)CD127 (low/-) T cells: a more specific Treg population in human peripheral blood. Inflammation. 2012; 35:1773–1780.

87. Dwyer KM, Hanidziar D, Putheti, et al. Expression of CD39 by human peripheral blood CD4+ CD25+ T cells denotes a regulatory memory phenotype. Am J Transplant. 2010; 10:2410–2420.

88. Doherty GA, Bai A, Hanidziar D, et al. CD73 is a phenotypic marker of effector memory Th17 cells in inflammatory bowel disease. Eur J Immunol. 2012; 42:3062–3072.

89. Collison LW, Vignali DA. In vitro Treg suppression assays. Methods Mol Biol. 2011; 707:21–37.

90. Gibbons DL, Spencer J. Mouse and human intestinal immunity: same ballpark, different players; different rules, same score. Mucosal Immunol. 2011; 4:148–157.

91. Oldenhove G, Bouladoux N, Wohlfert EA, et al. Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity. 2009; 31:772–786.

92. Wohlfert E, Belkaid Y. Plasticity of T reg at infected sites. Mucosal Immunol. 2010; 3:213–215.

93. Liu W, Putnam AL, Xu-Yu Z, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006; 203:1701–1711.

94. Scotta C, Esposito M, Fazekasova H, et al. Differential effects of rapamycin and retinoic acid on expansion, stability and suppressive qualities of human CD4+ CD25+FOXP3+ Treg subpopulations. Haematologica. 2013; 98:1291–1299.

95. Sandborn WJ, Feagan BG, Fedorak RN, et al. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology. 2008; 135:1130–1141.

96. Sandborn WJ, Gasink C, Gao LL, et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. New Engl J Med. 2012; 367:1519–1528.

97. Geuking MB, Cahenzli J, Lawson MA, et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity. 2011; 34:794–806.

98. Round JL, Lee SM, Li J, et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science. 2011; 332:974–977.

99. Desreumaux P, Foussat A, Allez M, et al. Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn’s disease. Gastroenterology. 2012; 143:1207–1217

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Keywords:

inflammatory bowel disease; anti-TNF treatment; immune system; Treg; FoxP3

Copyright © 2013 Crohn's & Colitis Foundation of America, Inc.

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