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• W1997714882 abstract "Allergic diseases and asthma are caused by dysregulated Th2-type immune responses, which drive disease development in susceptible individuals. Immune tolerance to allergens prevents inflammatory symptoms in the respiratory mucosa and provides protection against inflammation in the airways. Increasing evidence indicates that Foxp3+ regulatory T cells (Tregs) play a critical role in immune tolerance and control Th2-biased responses. Tregs develop in the thymus from CD4+ T cells (natural Tregs) and also in the periphery by the conversion of naïve CD4+ T cells (induced Tregs). Increased susceptibility to allergy and airway inflammation is hypothesized to result from impaired development and function of Tregs. Thus, strategies to induce allergen-specific Tregs hold great promise for treatment and prevention of asthma. Allergic diseases and asthma are caused by dysregulated Th2-type immune responses, which drive disease development in susceptible individuals. Immune tolerance to allergens prevents inflammatory symptoms in the respiratory mucosa and provides protection against inflammation in the airways. Increasing evidence indicates that Foxp3+ regulatory T cells (Tregs) play a critical role in immune tolerance and control Th2-biased responses. Tregs develop in the thymus from CD4+ T cells (natural Tregs) and also in the periphery by the conversion of naïve CD4+ T cells (induced Tregs). Increased susceptibility to allergy and airway inflammation is hypothesized to result from impaired development and function of Tregs. Thus, strategies to induce allergen-specific Tregs hold great promise for treatment and prevention of asthma. The incidence of chronic inflammatory lung diseases, such as asthma, has increased dramatically in recent years in industrialized countries. Asthma is characterized by airway hyperresponsiveness, chronic pulmonary eosinophilia, elevated serum IgE, excessive mucus production, and airway remodeling.1Herrick CA Bottomly K To respond or not to respond: t cells in allergic asthma.Nat Rev Immunol. 2003; 3: 405-412Crossref PubMed Scopus (300) Google Scholar These symptoms are believed to result from interactions between environmental stimuli and a variety of genes influencing immune and respiratory function. In susceptible individuals, environmental stimuli induce immune dysfunction, which drives Th2 responses to otherwise harmless antigens. Although it is clear that Th2 responses drive pathological changes in asthma, the mechanisms that develop in vivo to prevent Th2-driven inflammation in nonallergic individuals are not clear. The identification of reciprocally inhibitory functions of Th1 and Th2 cells led to the concept that a defect in Th1-type immune responses resulted in deregulated Th2 responses and increased incidence of allergic diseases. Based on this concept, the hygiene hypothesis was proposed, which posits that decreased exposure to Th1-inducing infections, such as mycobacteria and viruses, leads to unconstrained development of Th2 responses and increased incidence of allergic diseases.1Herrick CA Bottomly K To respond or not to respond: t cells in allergic asthma.Nat Rev Immunol. 2003; 3: 405-412Crossref PubMed Scopus (300) Google Scholar, 2Shirakawa T Enomoto T Shimazu S Hopkin JM The inverse association between tuberculin responses and atopic disorder.Science. 1997; 275: 77-79Crossref PubMed Scopus (1167) Google Scholar However, this simple explanation is insufficient to explain many experimental findings. First, Th1-responding cells are not always beneficial in allergic asthma and have been reported to contribute to and exacerbate this disease.3Hansen G Berry G DeKruyff RH Umetsu DT Allergen-specific Th1 cells fail to counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation.J Clin Invest. 1999; 103: 175-183Crossref PubMed Scopus (581) Google Scholar, 4Dahl ME Dabbagh K Liggitt D Kim S Lewis DB Viral-induced T helper type 1 responses enhance allergic disease by effects on lung dendritic cells.Nat Immunol. 2004; 5: 337-343Crossref PubMed Scopus (188) Google Scholar For example, adoptive transfer of Th1 cells resulted in enhanced airway eosinophilia and Th2 responses.5Randolph DA Stephens R Carruthers CJ Chaplin DD Cooperation between Th1 and Th2 cells in a murine model of eosinophilic airway inflammation.J Clin Invest. 1999; 104: 1021-1029Crossref PubMed Scopus (294) Google Scholar Similarly, inhaled recombinant interferon-γ did not significantly alter clinical symptoms in humans.6Martin RJ Boguniewicz M Henson JE Celniker AC Williams M Giorno RC Leung DY The effects of inhaled interferon gamma in normal human airways.Am Rev Respir Dis. 1993; 148: 1677-1682Crossref PubMed Google Scholar Second, epidemiological data suggest a parallel increase in Th2-mediated allergic diseases and Th1-mediated autoimmune diseases, such as Type 1 diabetes, multiple sclerosis, and rheumatoid arthritis.7Sheikh A Smeeth L Hubbard R There is no evidence of an inverse relationship between TH2-mediated atopy and TH1-mediated autoimmune disorders: lack of support for the hygiene hypothesis.J Allergy Clin Immunol. 2003; 111: 131-135Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar These findings suggest that other regulatory mechanisms play a critical role in inhibiting the development of inappropriate Th2 (and Th1) responses. The respiratory mucosal surface is exposed to a vast quantity of environmental antigens, which challenge the immune system. Thus, the immune system must discriminate between, and appropriately respond to, both pathogenic and innocuous antigens. Under nonallergic circumstances, soluble proteins do not provoke a strong immune response, but instead induce a state of antigen-specific tolerance or hyporesponsiveness. T cell tolerance is achieved through central and peripheral mechanisms. Central tolerance encompasses deletion of T cells during negative selection, as well as selection of Tregs in the thymus. On the other hand, peripheral tolerance encompasses the mechanisms that lead to T cell tolerance to antigens; these include ignorance, deletion, anergy induction, and active suppression by CD4+Foxp3+ regulatory T cells (Tregs). There is growing evidence that Tregs play an important role in inhibiting Th2-mediated responses to allergens and maintaining immune tolerance. Studies in mouse models have shown that peripheral CD4+ T cell tolerance, induced by respiratory exposure to allergens, prevents the development of allergen-induced airway hyperresponsiveness.8Umetsu DT DeKruyff RH The regulation of allergy and asthma.Immunol Rev. 2006; 212: 238-255Crossref PubMed Scopus (206) Google Scholar Likewise, we have reported that intravenous administration of soluble antigens results in antigen-specific anergy in Th2 cells and reduces airway inflammation.9Venuprasad K Elly C Gao M Salek-Ardakani S Harada Y Luo JL Yang C Croft M Inoue K Karin M Liu YC Convergence of Itch-induced ubiquitination with MEKK1-JNK signaling in Th2 tolerance and airway inflammation.J Clin Invest. 2006; 116: 1117-1126Crossref PubMed Scopus (83) Google Scholar In this review we summarize current knowledge of Treg development and their role in the regulation of Th2-mediated allergic responses. Tregs develop in the thymus from CD4 single positive thymocytes (called natural Tregs or nTregs), and also in the periphery by the conversion of naïve CD4 T cells in response to specific tolerogenic stimuli (called induced Tregs or iTregs). Although there is consensus that nTregs develop early to suppress autoimmune responses, as recently reviewed by Kong et al,10Kong Y Morris GP Brown NK Yan Y Flynn JC David CS Autoimmune thyroiditis: a model uniquely suited to probe regulatory T cell function.J Autoimmun. 2009; 33: 239-246Crossref PubMed Scopus (40) Google Scholar it is presently unclear whether nTregs and iTregs serve different physiological needs or have some redundant functions. Moreover, their relative contribution to the total pool of Tregs in secondary lymphoid organs or nonlymphoid tissues during the course of immune challenge remains to be determined. The notion that Tregs develop in the thymus came from neonatal thymectomy experiments. Thymectomy at day 3 after birth in normal mice resulted in autoimmune damage of various organs, such as the thyroid, stomach, and ovaries. Inoculation of normal CD4+ T cells and CD4+CD8- thymocytes inhibited the development of autoimmunity.11Sakaguchi S Yamaguchi T Nomura T Ono M Regulatory T cells and immune tolerance.Cell. 2008; 133: 775-787Abstract Full Text Full Text PDF PubMed Scopus (3681) Google Scholar These studies suggested that normal animals harbor not only pathogenic, self-reactive T cells but also inhibitory T cells that suppress immune responses detrimental to self. Subsequent efforts to identify Tregs resulted in the elucidation of first CD412Kong YM Giraldo AA Waldmann H Cobbold SP Fuller BE Resistance to experimental autoimmune thyroiditis: l3T4+ cells as mediators of both thyroglobulin-activated and TSH-induced suppression.Clin Immunol Immunopathol. 1989; 51: 38-54Crossref PubMed Scopus (58) Google Scholar, 13Sakaguchi S Sakaguchi N Asano M Itoh M Toda M Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.J Immunol. 1995; 155: 1151-1164PubMed Google Scholar and then CD25, as the specific Treg markers. These CD4+CD25+Tregs constitute approximately 5 to 15% of peripheral CD4+ T cells and play a nonredundant role in maintaining immunological self-tolerance and homeostasis of the immune network.11Sakaguchi S Yamaguchi T Nomura T Ono M Regulatory T cells and immune tolerance.Cell. 2008; 133: 775-787Abstract Full Text Full Text PDF PubMed Scopus (3681) Google Scholar Tregs express the Fork-head transcription factor Foxp3, which was first identified as the defective gene responsible for wide spread autoimmune disease in scurfy mice and in humans with IPEX, the immune dysregulation, polyendocrinopathy, enteropathy, and x-linked syndrome.11Sakaguchi S Yamaguchi T Nomura T Ono M Regulatory T cells and immune tolerance.Cell. 2008; 133: 775-787Abstract Full Text Full Text PDF PubMed Scopus (3681) Google Scholar Foxp3 is specifically expressed in CD4+CD25+ Tregs and ectopic expression of Foxp3 in CD4+CD25− cells converts them into Tregs, capable of suppressing proliferation of other T cells in vitro and inhibiting autoimmunity in vivo.14Burchill MA Yang J Vang KB Farrar MA Interleukin-2 receptor signaling in regulatory T cell development and homeostasis.Immunol Lett. 2007; 114: 1-8Crossref PubMed Scopus (149) Google Scholar Despite our growing knowledge of Treg biology, the molecular mechanism that regulates expression of Foxp3 in Tregs during their development is not fully understood. Studies have suggested that nTregs develop from CD4 single positive thymocytes, which acquire Foxp3 expression during ontogeny. More recent work from our lab and that of Chyi Hsieh’s has demonstrated that Tregs undergo development via a two-step process.15Burchill MA Yang J Vang KB Moon JJ Chu HH Lio CW Vegoe AL Hsieh CS Jenkins MK Farrar MA Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire.Immunity. 2008; 28: 112-121Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar, 16Lio CW Hsieh CS A two-step process for thymic regulatory T cell development.Immunity. 2008; 28: 100-111Abstract Full Text Full Text PDF PubMed Scopus (472) Google Scholar The first step requires TCR/MHC II16Lio CW Hsieh CS A two-step process for thymic regulatory T cell development.Immunity. 2008; 28: 100-111Abstract Full Text Full Text PDF PubMed Scopus (472) Google Scholar and CD28-dependent signals,17Vang KB, Yang J, Pagan AJ, Li LX, Wang J, Green JM, Beg AA, Farrar MA: CD28 and c-Rel-dependent pathways initiate regulatory T cell development. J Immunol 2010, in pressGoogle Scholar which results in the generation of a CD4+CD25+CD122+GITRhiFoxp3− Treg progenitor. The effect of CD28 appears to involve the nuclear factor (NF)κB pathway, as CD28 knock-in mice defective in NFκB activation exhibit a clear reduction in Tregs. Consistent with this notion, carma1−/− mice also lack Treg progenitors18Molinero LL Yang J Gajewski T Abraham C Farrar MA Alegre ML CARMA1 controls an early checkpoint in the thymic development of FoxP3+ regulatory T cells.J Immunol. 2009; 182: 6736-6743Crossref PubMed Scopus (87) Google Scholar; this appears to reflect a specific role for c-Rel, as c-rel−/− but not NFκB1−/− mice lack Tregs19Long M Park SG Strickland I Hayden MS Ghosh S Nuclear factor-kappaB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor.Immunity. 2009; 31: 921-931Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar, 20Ruan Q Kameswaran V Tone Y Li L Liou HC Greene MI Tone M Chen YH Development of Foxp3(+) regulatory t cells is driven by the c-Rel enhanceosome.Immunity. 2009; 31: 932-940Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar and Treg progenitors.17Vang KB, Yang J, Pagan AJ, Li LX, Wang J, Green JM, Beg AA, Farrar MA: CD28 and c-Rel-dependent pathways initiate regulatory T cell development. J Immunol 2010, in pressGoogle Scholar Thus, the molecular mechanisms underlying the development of Treg progenitors are just beginning to be characterized. The second step of Treg development involves cytokine-dependent conversion of Treg progenitors into mature Foxp3+ Tregs. This is consistent with the observation that interleukin (IL)-2R γc−/− mice are devoid of Tregs.14Burchill MA Yang J Vang KB Farrar MA Interleukin-2 receptor signaling in regulatory T cell development and homeostasis.Immunol Lett. 2007; 114: 1-8Crossref PubMed Scopus (149) Google Scholar IL-2 is likely the only physiologically relevant cytokine involved in this process. Several pieces of evidence support this statement. First, IL-2 is by far the most effective cytokine at driving the conversion of sorted Treg progenitors into mature Tregs in vitro; IL-7 and IL-15 also can do this, but quite poorly.16Lio CW Hsieh CS A two-step process for thymic regulatory T cell development.Immunity. 2008; 28: 100-111Abstract Full Text Full Text PDF PubMed Scopus (472) Google Scholar, 21Vang KB Yang J Mahmud SA Burchill MA Vegoe AL Farrar MA IL-2, -7, and -15, but not thymic stromal lymphopoeitin, redundantly govern CD4+Foxp3+ regulatory T cell development.J Immunol. 2008; 181: 3285-3290PubMed Google Scholar Second, although Tregs can be observed in il2−/− and il2rα−/− mice, these Tregs show aberrantly high expression of IL-7Rα and IL-15Rα chains; short-term exposure of Tregs obtained from il2−/− mice to IL-2 rapidly reduces expression of both cytokine receptors.21Vang KB Yang J Mahmud SA Burchill MA Vegoe AL Farrar MA IL-2, -7, and -15, but not thymic stromal lymphopoeitin, redundantly govern CD4+Foxp3+ regulatory T cell development.J Immunol. 2008; 181: 3285-3290PubMed Google Scholar Finally, in mixed bone marrow chimeras using wild-type and il2rα−/− bone marrow, only the wild-type bone marrow-derived cells effectively generated Tregs.22Fontenot JD Rasmussen JP Gavin MA Rudensky AY A function for interleukin 2 in Foxp3-expressing regulatory T cells.Nat Immunol. 2005; 6: 1142-1151Crossref PubMed Scopus (1419) Google Scholar Thus, under physiological conditions, IL-2 appears to be the only cytokine that effectively drives Treg development. The process by which IL-2 drives Treg development appears to uniquely require IL-2-dependent activation of the downstream transcription factor, signal transducer and activator of transcription (STAT)5. Mice that lack STAT5 are devoid of Tregs, while transgenic mice expressing a constitutively active form of STAT5 (called STAT5b-CA) have a greatly expanded population of Tregs.23Burchill MA Yang J Vogtenhuber C Blazar BR Farrar MA IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells.J Immunol. 2007; 178: 280-290PubMed Google Scholar Moreover, mice expressing IL-2Rβ mutants that can only activate the STAT5 pathway still have Tregs, and crossing the STAT5b-CA transgenic mice to il2rβ−/− mice rescues the defect in Treg development normally seen in il2rβ−/− mice.23Burchill MA Yang J Vogtenhuber C Blazar BR Farrar MA IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells.J Immunol. 2007; 178: 280-290PubMed Google Scholar Intriguingly, the STAT5-dependent conversion of Treg progenitors into mature Tregs is blocked by histone deacetylase inhibitors.15Burchill MA Yang J Vang KB Moon JJ Chu HH Lio CW Vegoe AL Hsieh CS Jenkins MK Farrar MA Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire.Immunity. 2008; 28: 112-121Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar The reason for this remains unknown. However, the most likely explanation is that STAT5/histone deacetylase interactions are required for foxp3 transcription; this could involve removal of inhibitory acetyl groups on other transcription factors required for foxp3 transcription or may involve a completely novel mechanism. A more controversial question involves the role of transforming growth factor (TGF)-β in Treg development. nTreg development was shown to be normal in both tgf-β−/− mice and tgf-β receptor knock-out mice.24Li MO Wan YY Sanjabi S Robertson AK Flavell RA Transforming growth factor-beta regulation of immune responses.Annu Rev Immunol. 2006; 24: 99-146Crossref PubMed Scopus (1742) Google Scholar Likewise, we and Chyi Hsieh and colleagues15Burchill MA Yang J Vang KB Moon JJ Chu HH Lio CW Vegoe AL Hsieh CS Jenkins MK Farrar MA Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire.Immunity. 2008; 28: 112-121Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar, 16Lio CW Hsieh CS A two-step process for thymic regulatory T cell development.Immunity. 2008; 28: 100-111Abstract Full Text Full Text PDF PubMed Scopus (472) Google Scholar found that in vitro conversion of thymic Treg progenitors into mature Tregs did not require TGF-β. However a separate study found that mice doubly deficient for TGF-β and IL-2 exhibit a severe defect in Treg development in the thymus,25Liu 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: 632-640Crossref PubMed Scopus (446) Google Scholar suggesting that IL-2 masks the effect of Treg deficiency by expanding the few Tregs that develop in tgfβ−/− mice. This finding appears to contradict the observation that conversion of thymic Treg progenitors into mature Tregs does not require TGF-β. However, these data would be reconciled if TGF-β influenced the development of Treg progenitors (step I of the Treg developmental process) but not the IL-2-driven conversion of those cells into mature Tregs (step II of the process). A final question involves the thymic niche where Treg development occurs. Recent work by Hsieh and colleagues26Bautista JL Lio CW Lathrop SK Forbush K Liang Y Luo J Rudensky AY Hsieh CS Intraclonal competition limits the fate determination of regulatory T cells in the thymus.Nat Immunol. 2009; 10: 610-617Crossref PubMed Scopus (199) Google Scholar has demonstrated that the thymic niche for Treg development is likely to be ∼100-fold smaller than that observed for positive selection. Specifically, mice expressing a TCR-transgene derived from nTreg can give rise to Tregs but only do so efficiently if present at very low clonal frequencies. In contrast, the OT-II TCR (specific for an MHC class II/ovalbumin peptide) transgene is incapable of giving rise to Tregs at any clonal frequency. This result suggests that Treg development requires both the appropriate TCR and also interaction with an easily saturable thymic niche. Whether the small size of this thymic Treg niche reflects limiting high affinity antigens, and/or limiting levels of IL-2 remains to be addressed. In addition to the thymic production of nTregs, naïve CD4+ T cells in the periphery acquire Foxp3 expression and Treg function in several experimental settings, namely in vitro antigen stimulation in the presence of TGF-β or chronic antigen stimulation in vivo.27Chen 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: 1875-1886Crossref PubMed Scopus (3797) Google Scholar, 28Apostolou I von Boehmer H In vivo instruction of suppressor commitment in naive T cells.J Exp Med. 2004; 199: 1401-1408Crossref PubMed Scopus (602) Google Scholar Such iTregs inhibit the development of autoimmunity and inflammation in allergic inflammation models.27Chen 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: 1875-1886Crossref PubMed Scopus (3797) Google Scholar For example, using a mouse model of hyper-IgE and asthma, Mucida et al29Mucida D Kutchukhidze N Erazo A Russo M Lafaille JJ Curotto de Lafaille MA Oral tolerance in the absence of naturally occurring Tregs.J Clin Invest. 2005; 115: 1923-1933Crossref PubMed Scopus (378) Google Scholar demonstrated that iTregs induced in the absence of nTregs effectively inhibit Th2 responses. To generate this model they crossed influenza Hemagglutinin-specific immunoglobulin heavy and light chain knock-in mice with DO11.10 OVA-specific TCR-transgenic mice on a rag-1 knock-out background. These mice develop an exacerbated Th2 response after immunization and respiratory challenge with cognate antigen complex OVA-Hemagglutinin.29Mucida D Kutchukhidze N Erazo A Russo M Lafaille JJ Curotto de Lafaille MA Oral tolerance in the absence of naturally occurring Tregs.J Clin Invest. 2005; 115: 1923-1933Crossref PubMed Scopus (378) Google Scholar However, oral antigen administration before immunization inhibited effector/memory Th2 cell development, class switching to IgE, and airway inflammation. This effect of oral antigen administration was due to the development of antigen-specific CD4+CD25+Foxp3+ Tregs independent of thymic Treg development. Similarly, it has been demonstrated that nTregs and de novo generated iTregs contribute independently to tumor-specific tolerance.30Zhou G Levitsky HI Natural regulatory T cells and de novo-induced regulatory T cells contribute independently to tumor-specific tolerance.J Immunol. 2007; 178: 2155-2162PubMed Google Scholar However, the extent to which such iTregs contribute to the peripheral pool of Tregs, and whether they have a stable phenotype comparable with that of nTregs, is not clear. This is partly due to a lack of reliable markers to distinguish nTregs and iTregs. Recent studies suggest that there are significant differences in the development, antigen specificity, and stability of suppressor function between nTregs and iTregs.31Horwitz DA Zheng SG Gray JD Natural and TGF-beta-induced Foxp3(+)CD4(+) CD25(+) regulatory T cells are not mirror images of each other.Trends Immunol. 2008; 29: 429-435Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar The development of nTregs requires high affinity interactions with cognate self peptide–MHC complexes and CD28 costimulation, whereas iTreg development requires weaker suboptimal TCR stimulation and costimulation through CTLA-4.32Zheng SG Wang JH Stohl W Kim KS Gray JD Horwitz DA TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+CD25+ regulatory cells.J Immunol. 2006; 176: 3321-3329PubMed Google Scholar In vitro studies further show that Foxp3 expression is relatively unstable in iTregs compared with nTregs; when iTregs are restimulated in the absence of TGF-β, they lose Foxp3 expression and inhibitory function.33Floess S Freyer J Siewert C Baron U Olek S Polansky J Schlawe K Chang HD Bopp T Schmitt E Klein-Hessling S Serfling E Hamann A Huehn J Epigenetic control of the foxp3 locus in regulatory T cells.PLoS Biol. 2007; 5: e38Crossref PubMed Scopus (959) Google Scholar This difference in the stability of Foxp3 expression is attributed to the methylation status of CpG motifs in the Foxp3 locus.33Floess S Freyer J Siewert C Baron U Olek S Polansky J Schlawe K Chang HD Bopp T Schmitt E Klein-Hessling S Serfling E Hamann A Huehn J Epigenetic control of the foxp3 locus in regulatory T cells.PLoS Biol. 2007; 5: e38Crossref PubMed Scopus (959) Google Scholar However, the full extent of differences and similarities between iTregs and nTregs is yet to be defined. Several studies have suggested that mucosal tissues are a major site of Foxp3+ iTreg development, and several micro-environmental factors may promote or inhibit iTreg development. The presence of IL-6 inhibits Foxp3 expression and promotes CD4+ T cell differentiation into Th17 effector cells.34Dong C TH17 cells in development: an updated view of their molecular identity and genetic programming.Nat Rev Immunol. 2008; 8: 337-348Crossref PubMed Scopus (865) Google Scholar Blockade of the IL-6 receptor led to expansion of CD4+CD25+ Tregs in the airway and suppressed airway inflammation.35Doganci A Eigenbrod T Krug N De Sanctis GT Hausding M Erpenbeck VJ Haddad el B Lehr HA Schmitt E Bopp T Kallen KJ Herz U Schmitt S Luft C Hecht O Hohlfeld JM Ito H Nishimoto N Yoshizaki K Kishimoto T Rose-John S Renz H Neurath MF Galle PR Finotto S The IL-6R alpha chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo.J Clin Invest. 2005; 115: 313-325Crossref PubMed Scopus (331) Google Scholar In addition to IL-6, it has been found that pro-inflammatory cytokines that drive Th1 and Th2 differentiation also inhibit iTreg development.36Zhou L Chong MM Littman DR Plasticity of CD4+ T cell lineage differentiation.Immunity. 2009; 30: 646-655Abstract Full Text Full Text PDF PubMed Scopus (1150) Google Scholar The vitamin A metabolite retinoic acid (RA) inhibits the IL-6–driven induction of TH17 cells and promotes anti-inflammatory Treg cell differentiation.37Mucida 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: 256-260Crossref PubMed Scopus (1606) Google Scholar CD103+ DCs isolated from the small intestine produce both TGF-β and RA, and these DCs efficiently promote Foxp3 expression and iTreg development.38Coombes JL Siddiqui KR Arancibia-Carcamo CV Hall J Sun CM Belkaid Y Powrie F A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism.J Exp Med. 2007; 204: 1757-1764Crossref PubMed Scopus (2166) Google Scholar, 39Sun CM Hall JA Blank RB Bouladoux N Oukka M Mora JR Belkaid Y Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid.J Exp Med. 2007; 204: 1775-1785Crossref PubMed Scopus (1500) Google Scholar RA was shown to enhance TGF-β-driven Smad3 signaling and inhibit IL-6 and IL-23 receptor expression.40Xiao S Jin H Korn T Liu SM Oukka M Lim B Kuchroo VK Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression.J Immunol. 2008; 181: 2277-2284PubMed Google Scholar On the other hand, Hill et al41Hill JA Hall JA Sun CM Cai Q Ghyselinck N Chambon P Belkaid Y Mathis D Benoist C Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+CD44hi Cells.Immunity. 2008; 29: 758-770Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar showed that, rather than enhancing TGF-β signaling directly in naïve CD4 T cells, RA negatively regulates accompanying CD4+CD44hi effector memory cells. These memory cells actively inhibited TGF-β effects through the secretion of a set of cytokines (IL-4, IL-21, and interferon-γ) whose expression was curtailed by RA. Further, using highly purified naive (CD4+CD25-CD44loCD62L+) CD4+T cells, Mucida et al42Mucida D Pino-Lagos K Kim G Nowak E Benson MJ Kronenberg M Noelle RJ Cheroutre H Retinoic acid can directly promote TGF-beta-mediated Foxp3(+) Treg cell conversion of naive T cells.Immunity. 2009; 30 (author reply 472–473): 471-472Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar reported that RA enhanced Foxp3 expression by acting both directly on naïve CD4 T cells and indirectly via inhibitory effects on CD4+CD44hi T cells. Taken together, the net outcome is likely determined by relative levels of various factors present in the tissue microenvironment during T cell activation. Despite the growing body of data regarding the role of Foxp3 in Treg development and function, relatively little is known about the transcriptional regulation of Foxp3. Specifically, what are the signals that regulate transcription of foxp3 in Tregs? The foxp3 promoter contains NFAT, AP-1, and SP1 binding sites and a TATA and CAAT box43Mantel PY Ouaked N Ruckert B Karagiannidis C Welz R Blaser K Schmidt-Weber CB Molecular mechanisms underlying FOXP3 induction in human T cells.J Immunol. 2006; 176: 3593-3602PubMed Google Scholar (Figure 1). The core promoter is located 6.5 kb upstream of the foxp3 translation start site and the 5′ untranslated region is interrupted by a 6000 bp intron.43Mantel PY Ouaked N Ruckert B Karagiannidis C Welz R Blaser K Schmidt-Weber CB Molecular mechanisms underlying FOXP3 induction in human T cells.J Immuno" @default.
• W1997714882 created "2016-06-24" @default.
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• W1997714882 creator A5019533468 @default.
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• W1997714882 date "2010-08-01" @default.
• W1997714882 modified "2023-10-02" @default.
• W1997714882 title "Control of Th2-Mediated Inflammation by Regulatory T Cells" @default.
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• W1997714882 doi "https://doi.org/10.2353/ajpath.2010.090936" @default.
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