IL-10 producing regulatory type 1 (TR1) T cells are instrumental in the prevention of tissue inflammation, autoimmunity and graft-versus-host disease. The transcription factor c-Maf is essential for TR1 induction of IL-10, but the molecular mechanisms leading to the development of these cells remain incompletely understood. We demonstrate that the ligand–activated transcription factor aryl hydrocarbon receptor (AhR) induced by IL-27, synergizes with c-Maf to promote the development of TR1 cells. Upon T cell activation under TR1-skewing conditions, the AhR binds to c-Maf and promotes the transactivation of both Il10 and Il21 promoters, resulting in the generation of TR1 cells and amelioration of experimental autoimmune encephalomyelitis. Manipulation of AhR signaling could therefore be beneficial in the resolution of excessive inflammatory responses.
The aryl hydrocarbon receptor (AhR) participates in the differentiation of mouse regulatory T cells (T reg cells) and interleukin 17 (IL-17)-producing helper T cells (T H 17 cells), but its role in human T cell differentiation is unknown. We investigated the role of AhR in the differentiation of human induced T reg cells (iT reg cells). We found that AhR activation promoted the differentiation of CD4 + Foxp3 − T cells, which produce IL-10 and control responder T cells through granzyme B. However, activation of AhR in the presence of transforming growth factor-β1 induced Foxp3 + iT reg cells, which suppress responder T cells through the ectonucleoside triphosphate diphosphohydrolase CD39. The induction of functional Foxp3 + iT reg cells required coordinated action of the transcriptional regulators Smad1 and Aiolos. Thus, AhR is a potential target through which functional iT reg cells could be induced in human autoimmune disorders.In healthy people, the immune response is controlled by several subsets of regulatory T cells (T reg cells) that are generated in the thymus (natural T reg ) and also in the periphery in response to various tolerogenic stimuli (induced T reg cells (iT reg cells) 1 . One of these subsets is a population of CD4 + T cells characterized by expression of the transcription factor Foxp3 (A002750) 1 . In mice, Foxp3 is a specific marker for T reg cells, and forced expression of Foxp3 (refs. 2,3 ) or its induction with transforming growth factor-β1 (TGF-β1) 4 promotes the differentiation of functional Foxp3 + T reg cells. In humans, however, Foxp3 expression is not always linked to regulatory function: activated T cells transiently express Foxp3 (refs. 5,6 ), and neither forced overexpression of Foxp3 (ref. 7 ) nor its induction with TGF-β1 (ref. 8 ) results in the differentiation of suppressive Foxp3 + T reg cells. Thus, additional signals beyond those controlled by Foxp3 are required for the generation of human functional Foxp3 + T reg cells.Correspondence should be addressed to F.J.Q. (fquintana@rics.bwh.harvard.edu). 3 Present address: Department of Neurosciences, Ophthalmology and Genetics, University of Genoa, Genoa, Italy.Accession codes. UCSD-Nature Signaling Gateway (http://www.signaling-gateway.org): A002750, A000229 and A003947.Note: Supplementary information is available on the Nature Immunology website. AUTHOR CONTRIBUTIONS COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests.Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/. NIH Public Access RESULTS AhR activation induces T cells that produce IL-10AhR participates in the differentiation of mouse Foxp3 + T reg cells [14][15][16][17][18] . To investigate whether AhR contributes to the differentiation of human T reg cells, we isolated naive CD4 + T cells from peripheral blood mononuclear cells obtained from healthy donors and activated them with anti-CD3, anti-CD28 and IL-2 with or without the AhR ligand TCDD ( Supplementary Fig. 1). Naive ...
In this study, we demonstrate that dedifferentiation of round primary chondrocytes into a fibroblast morphology correlates with a profound induction of RhoA protein and stress fibers. Culture of dedifferentiated chondrocytes in alginate gel induces a precipitous loss of RhoA protein and a loss of stress fibers concomitant with the reexpression of the chondrocyte differentiation program. We have found that chondrogenesis in limb bud micromass cultures similarly entails a loss of RhoA protein and that expression of dominant negative RhoA in such cultures can markedly enhance chondrogenesis. Consistent with these results, expression of the Rho antagonist C3 transferase can restore chondrocyte gene expression in dedifferentiated chondrocytes grown on plastic. Transfection of cells with agents that block actin polymerization enhance the ability of either exogenous Sox9 or a Gal4 DBD-Sox9 fusion protein to activate gene expression. Interestingly, the enhancement of Sox9 function by actin depolymerization requires both protein kinase A (PKA) activity and a PKA phosphorylation site in Sox9 (S181) that is known to enhance Sox9 transcriptional activity. Lastly, we demonstrate that RhoA-mediated modulation of actin polymerization regulates the ability of Sox9 to both activate chondrocyte-specific markers and maintain its own expression in chondrocytes via a positive feedback loop.Vertebrate long bones are formed through a process of endochondral ossification (8,11). During this process, bone formation begins with the establishment of mesenchymal condensations, which serve as a template for the adult skeletal elements. Chondrocytes then differentiate within the aggregated mesenchyme, generating distinct cartilage primordia that begin longitudinal growth. A very important system to study the events that control the initiation of chondrocyte differentiation is the limb bud micromass culture system. Originally developed by Solursh and colleagues, this culture system employs mesenchymal cells isolated from either chick or mouse embryo limb buds, which undergo chondrogenesis when cultured under conditions of extremely high cell density, termed micromass culture (1,22). Recently, it was demonstrated that bone morphogenic protein (BMP) signaling is necessary for the initial compaction of limb bud mesenchymal cells into cellular condensations (2). After compaction, the limb bud cells that undergo chondrogenesis assume a round cell shape and coalesce to form a cartilage nodule (1, 2). For many years, it has been appreciated that environmental factors that alter either the cell shape or the actin cytoskeleton can modulate the ability of prechondrogenic cells to undergo chondrogenesis. It was initially noted that in vitro differentiation of limb bud mesenchymal cells into chondrocytes required that these cells be plated at a very high cell density (1, 22), presumably to promote cell-cell interactions. Interestingly, however, chondrogenesis could be induced in low-density cultures of limb bud mesenchymal cells when these cells were pla...
IL-22 produced by innate lymphoid cells (ILCs) and CD4+ T cells plays an important role in host defense and mucosal homeostasis, thus it is important to investigate the mechanisms that regulate IL-22 production. We investigated the regulation IL-22 production by CD4+ T cells. Here we show that IL-21 triggers IL-22, but not IL-17 production by CD4+ T cells. STAT3, activated by IL-21, controls the epigenetic status of the il22 promoter and its interaction with the aryl hydrocarbon receptor (AhR). Moreover, IL-21 and AhR signaling in T cells control IL-22 production and the development of dextran sodium sulfate-induced colitis in ILC-deficient mice. Thus, we have identified IL-21 as an inducer of IL-22 production in CD4+ T cells in vitro and in vivo.
INTRODUCTIONPax3 and Pax7 are two closely related transcription factors that are expressed in the dermomyotome, and they have been shown to be essential for generation of all fetal trunk musculature . Pax3/7-expressing dermomyotomal cells have recently been shown to give rise to skeletal muscle progenitors, termed satellite cells, in the adult (Gros et al., 2005;Kassar-Duchossoy et al., 2005;Relaix et al., 2005;Schienda et al., 2006). Satellite cells are a small population of myogenic progenitors that reside between the sarcolemma and basal lamina of the muscle fiber, and they play a crucial role in postnatal muscle growth and regeneration (reviewed in Zammit et al., 2006). Following skeletal muscle injury or exercise-induced activation, the normally quiescent Pax7-expressing satellite cells proliferate extensively and up-regulate expression of MyoD (Smith et al., 2001;Yan et al., 2003;Montarras et al., 2005) and Myf-5 (Conboy and Rando, 2002;Yan et al., 2003), before differentiation into skeletal muscle.Pax3 and Pax7 are members of the Pax transcription factor family and contain both paired (PD) and homeodomain (HD) DNA binding motifs. Pax3 and Pax7 can bind to DNA sequences containing either a consensus paired domain binding site (GTCAC A/G C/G A/T T/C) or a homeodomain binding site (ATTA) (Chalepakis et al., 1994;Chalepakis and Gruss, 1995). Pax3 and Pax7 activate MyoD expression (Maroto et al., 1997;Tajbakhsh et al., 1997;Relaix et al., 2003Relaix et al., , 2004, and recently Pax3 has been shown to directly bind sequences that regulate the expression of either MyoD in C2C12 cells (Hu et al., 2008) or Myf-5 during development of hypaxial muscle (Bajard et al., 2006). Although it is clear that Pax3/7 can directly induce the expression of Myf5 (Bajard et al., 2006), MyoD (Hu et al., 2008), and fibroblast growth factor receptor 4 (Lagha et al., 2008), other relevant targets for Pax3/7 in satellite cells have yet to be identified. To identify potential targets for Pax3/7 in satellite cells, we examined the transcriptional profile of genes induced by these transcription factors in the C2C12 muscle cell line. Of the genes identified, we found that a subset were also expressed in quiescent satellite cells and therefore they could potentially be direct targets of Pax7 in these cells. In this report, we focus on two such putative Pax3/7 transcriptional targets, inhibitor of DNA binding (Id) 2 and Id3, which we found to be expressed in quiescent satellite cells. We report that Pax3/7 can drive expression of both Id2 and Id3 in C2C12 cells under low serum conditions, that the Id3 promoter contains a conserved Pax3/7 binding site, and that Pax3/7 can activate expression of a reporter construct driven by the Id3 promoter. In addition, we demonstrate that Pax7 is normally bound to the Id3 promoter in quiescent satellite cells and that short hairpin RNA (shRNA)-mediated knockdown of Pax7 expression in cultured satellite cells Abbreviations used: C1R, complement component 1 R subunit; ChIP, chromatin immunoprecipitation; CS...
BackgroundThe dorsal midline region of the neural tube that results from closure of the neural folds is generally termed the roof plate (RP). However, this domain is highly dynamic and complex, and is first transiently inhabited by prospective neural crest (NC) cells that sequentially emigrate from the neuroepithelium. It only later becomes the definitive RP, the dorsal midline cells of the spinal cord. We previously showed that at the trunk level of the axis, prospective RP progenitors originate ventral to the premigratory NC and progressively reach the dorsal midline following NC emigration. However, the molecular mechanisms underlying the end of NC production and formation of the definitive RP remain virtually unknown.ResultsBased on distinctive cellular and molecular traits, we have defined an initial NC and a subsequent RP stage, allowing us to investigate the mechanisms responsible for the transition between the two phases.We demonstrate that in spite of the constant production of BMP4 in the dorsal tube at both stages, RP progenitors only transiently respond to the ligand and lose competence shortly before they arrive at their final location. In addition, exposure of dorsal tube cells at the NC stage to high levels of BMP signaling induces premature RP traits, such as Hes1/Hairy1, while concomitantly inhibiting NC production. Reciprocally, early inhibition of BMP signaling prevents Hairy1 mRNA expression at the RP stage altogether, suggesting that BMP is both necessary and sufficient for the development of this RP-specific trait.Furthermore, when Hes1/Hairy1 is misexpressed at the NC stage, it inhibits BMP signaling and downregulates BMPR1A/Alk3 mRNA expression, transcription of BMP targets such as Foxd3, cell-cycle progression, and NC emigration. Reciprocally, Foxd3 inhibits Hairy1, suggesting that repressive cross-interactions at the level of, and downstream from, BMP ensure the temporal separation between both lineages.ConclusionsTogether, our data suggest that BMP signaling is important both for NC and RP formation. Given that these two structures develop sequentially, we speculate that the longer exposure of RP progenitors to BMP compared with that of premigratory NC cells may be translated into a higher signaling level in the former. This induces changes in responsiveness to BMP, most likely by downregulating the expression of Alk3 receptors and, consequently, of BMP-dependent downstream transcription factors, which exhibit spatial complementary expression patterns and mutually repress each other to generate alternative fates. This molecular dynamic is likely to account for the transition between the NC and definitive RP stages and thus be responsible for the segregation between central and peripheral lineages during neural development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-016-0245-6) contains supplementary material, which is available to authorized users.
Epidemiological studies indicate an inverse correlation between the prevalence of the so-called western diseases, such as obesity and metabolic syndrome, and the exposure to helminths. Obesity, a key risk factor for many chronic health problems, is rising globally and is accompanied by low-grade inflammation in adipose tissues. The precise mechanism by which helminths modulate metabolic syndrome and obesity is not fully understood. We infected high fat diet (HFD)-induced obese mice with the intestinal nematode parasite Heligmosomoides polygyrus and observed that helminth infection resulted in significantly attenuated obesity. Attenuated obesity corresponded with marked upregulation of uncoupling protein 1 (UCP1), a key protein involved in energy expenditure, in adipose tissue, suppression of glucose and triglyceride levels, and alteration in the expression of key genes involved in lipid metabolism. Moreover, the attenuated obesity in infected mice was associated with enhanced helminth-induced Th2/Treg responses and M2 macrophage polarization. Adoptive transfer of helminth-stimulated M2 cells to mice that were not infected with H. polygyrus resulted in a significant amelioration of HFD-induced obesity and increased adipose tissue browning. Thus, our results provide evidence that the helminth-dependent protection against obesity involves the induction of M2 macrophages.
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