共查询到20条相似文献,搜索用时 249 毫秒
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Foxp3-dependent programme of regulatory T-cell differentiation 总被引:1,自引:0,他引:1
Gavin MA Rasmussen JP Fontenot JD Vasta V Manganiello VC Beavo JA Rudensky AY 《Nature》2007,445(7129):771-775
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TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function 总被引:2,自引:0,他引:2
Zhou L Lopes JE Chong MM Ivanov II Min R Victora GD Shen Y Du J Rubtsov YP Rudensky AY Ziegler SF Littman DR 《Nature》2008,453(7192):236-240
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Nurieva R Yang XO Martinez G Zhang Y Panopoulos AD Ma L Schluns K Tian Q Watowich SS Jetten AM Dong C 《Nature》2007,448(7152):480-483
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Dawson MA Prinjha RK Dittmann A Giotopoulos G Bantscheff M Chan WI Robson SC Chung CW Hopf C Savitski MM Huthmacher C Gudgin E Lugo D Beinke S Chapman TD Roberts EJ Soden PE Auger KR Mirguet O Doehner K Delwel R Burnett AK Jeffrey P Drewes G Lee K Huntly BJ Kouzarides T 《Nature》2011,478(7370):529-533
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Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression 总被引:1,自引:0,他引:1
The naturally occurring regulatory T cell (T(r)) is the pivotal cell type that maintains self-tolerance and exerts active immune suppression. The development and function of T(r) cells is controlled by Foxp3 (refs 1, 2), a lack of which results in loss of T(r) cells and massive multi-organ autoimmunity in scurfy mice and IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) patients. It is generally thought that, through a binary mechanism, Foxp3 expression serves as an on-and-off switch to regulate positively the physiology of T(r) cells; however, emerging evidence associates decreased Foxp3 expression in T(r) cells with various immune disorders. We hypothesized that Foxp3 regulates T(r) cell development and function in a dose-dependent, non-binary manner, and that decreased Foxp3 expression can cause immune disease. Here, by generating a mouse model in which endogenous Foxp3 gene expression is attenuated in T(r) cells, we show that decreased Foxp3 expression results in the development of an aggressive autoimmune syndrome similar to that of scurfy mice, but does not affect thymic development, homeostatic expansion/maintenance or transforming-growth-factor-beta-induced de novo generation of Foxp3-expressing cells. The immune-suppressive activities of T cells with attenuated Foxp3 expression were nearly abolished in vitro and in vivo, whereas their anergic properties in vitro were maintained. This was accompanied by decreased expression of T(r) cell 'signature genes'. Notably, T cells expressing decreased Foxp3 preferentially became T-helper 2 (T(h)2)-type effectors even in a T(h)1-polarizing environment. These cells instructed T(h)2 differentiation of conventional T cells, which contributed to the immune diseases observed in these mice. Thus, decreased Foxp3 expression causes immune disease by subverting the suppressive function of T(r) cells and converting T(r) cells into effector cells; these findings are important for understanding the regulation of T(r) cell function and the aetiology of various human immune diseases. 相似文献
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A c-myc antisense oligodeoxynucleotide inhibits entry into S phase but not progress from G0 to G1 总被引:12,自引:0,他引:12
R Heikkila G Schwab E Wickstrom S L Loke D H Pluznik R Watt L M Neckers 《Nature》1987,328(6129):445-449
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Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells 总被引:5,自引:0,他引:5
Bettelli E Carrier Y Gao W Korn T Strom TB Oukka M Weiner HL Kuchroo VK 《Nature》2006,441(7090):235-238
On activation, T cells undergo distinct developmental pathways, attaining specialized properties and effector functions. T-helper (T(H)) cells are traditionally thought to differentiate into T(H)1 and T(H)2 cell subsets. T(H)1 cells are necessary to clear intracellular pathogens and T(H)2 cells are important for clearing extracellular organisms. Recently, a subset of interleukin (IL)-17-producing T (T(H)17) cells distinct from T(H)1 or T(H)2 cells has been described and shown to have a crucial role in the induction of autoimmune tissue injury. In contrast, CD4+CD25+Foxp3+ regulatory T (T(reg)) cells inhibit autoimmunity and protect against tissue injury. Transforming growth factor-beta (TGF-beta) is a critical differentiation factor for the generation of T(reg) cells. Here we show, using mice with a reporter introduced into the endogenous Foxp3 locus, that IL-6, an acute phase protein induced during inflammation, completely inhibits the generation of Foxp3+ T(reg) cells induced by TGF-beta. We also demonstrate that IL-23 is not the differentiation factor for the generation of T(H)17 cells. Instead, IL-6 and TGF-beta together induce the differentiation of pathogenic T(H)17 cells from naive T cells. Our data demonstrate a dichotomy in the generation of pathogenic (T(H)17) T cells that induce autoimmunity and regulatory (Foxp3+) T cells that inhibit autoimmune tissue injury. 相似文献
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Collison LW Workman CJ Kuo TT Boyd K Wang Y Vignali KM Cross R Sehy D Blumberg RS Vignali DA 《Nature》2007,450(7169):566-569
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Mangan PR Harrington LE O'Quinn DB Helms WS Bullard DC Elson CO Hatton RD Wahl SM Schoeb TR Weaver CT 《Nature》2006,441(7090):231-234
A new lineage of effector CD4+ T cells characterized by production of interleukin (IL)-17, the T-helper-17 (T(H)17) lineage, was recently described based on developmental and functional features distinct from those of classical T(H)1 and T(H)2 lineages. Like T(H)1 and T(H)2, T(H)17 cells almost certainly evolved to provide adaptive immunity tailored to specific classes of pathogens, such as extracellular bacteria. Aberrant T(H)17 responses have been implicated in a growing list of autoimmune disorders. T(H)17 development has been linked to IL-23, an IL-12 cytokine family member that shares with IL-12 a common subunit, IL-12p40 (ref. 8). The IL-23 and IL-12 receptors also share a subunit, IL-12Rbeta1, that pairs with unique, inducible components, IL-23R and IL-12Rbeta2, to confer receptor responsiveness. Here we identify transforming growth factor-beta (TGF-beta) as a cytokine critical for commitment to T(H)17 development. TGF-beta acts to upregulate IL-23R expression, thereby conferring responsiveness to IL-23. Although dispensable for the development of IL-17-producing T cells in vitro and in vivo, IL-23 is required for host protection against a bacterial pathogen, Citrobacter rodentium. The action of TGF-beta on naive T cells is antagonized by interferon-gamma and IL-4, thus providing a mechanism for divergence of the T(H)1, T(H)2 and T(H)17 lineages. 相似文献
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RNA polymerase II elongation through chromatin 总被引:21,自引:0,他引:21
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Korn T Bettelli E Gao W Awasthi A Jäger A Strom TB Oukka M Kuchroo VK 《Nature》2007,448(7152):484-487
On activation, naive T cells differentiate into effector T-cell subsets with specific cytokine phenotypes and specialized effector functions. Recently a subset of T cells, distinct from T helper (T(H))1 and T(H)2 cells, producing interleukin (IL)-17 (T(H)17) was defined and seems to have a crucial role in mediating autoimmunity and inducing tissue inflammation. We and others have shown that transforming growth factor (TGF)-beta and IL-6 together induce the differentiation of T(H)17 cells, in which IL-6 has a pivotal function in dictating whether T cells differentiate into Foxp3+ regulatory T cells (T(reg) cells) or T(H)17 cells. Whereas TGF-beta induces Foxp3 and generates T(reg) cells, IL-6 inhibits the generation of T(reg) cells and induces the production of IL-17, suggesting a reciprocal developmental pathway for T(H)17 and T(reg) cells. Here we show that IL-6-deficient (Il6-/-) mice do not develop a T(H)17 response and their peripheral repertoire is dominated by Foxp3+ T(reg) cells. However, deletion of T(reg) cells leads to the reappearance of T(H)17 cells in Il6-/- mice, suggesting an additional pathway by which T(H)17 cells might be generated in vivo. We show that an IL-2 cytokine family member, IL-21, cooperates with TGF-beta to induce T(H)17 cells in naive Il6-/- T cells and that IL-21-receptor-deficient T cells are defective in generating a T(H)17 response. 相似文献
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Regulation of T-cell receptor gamma-chain RNA expression in murine Thy-1+ dendritic epidermal cells 总被引:1,自引:0,他引:1
W A Kuziel A Takashima M Bonyhadi P R Bergstresser J P Allison R E Tigelaar P W Tucker 《Nature》1987,328(6127):263-266
The epidermis of normal mice contains two distinct populations of dendritic cells derived from the bone marrow, Ia+ Langerhans cells and Ia- cells that express the Thy-1 alloantigen. The Thy-1-bearing dendritic epidermal cells (Thy-1+ dEC) have a surface phenotype similar to that of very early T-lineage cells, produce IL-2-like growth factors and exhibit cytotoxicity which is not restricted by the major histocompatibility complex (MHC). The relationship of Thy-1+ dEC to the T-cell lineage is unclear. Most T lymphocytes bear a receptor for antigen composed of an alpha chain and a beta chain associated with a nonpolymorphic complex termed CD3 (T3). A minor population carries a receptor in which CD3 is associated with a gamma/delta complex. We have analysed clones of Thy-1+ dEC for rearrangement and expression of the genes for the alpha-, beta- and gamma-chains of the T-cell receptor (TCR). They do not express alpha or beta but do carry a gamma/delta complex. Activation of the cells with Con A is associated with a rapid decrease in the steady-state level of gamma-chain RNA. Because Thy-1+ dEC resemble early stage T lymphocytes, down-regulation of TCR expression may reflect a necessary event during T cell differentiation. 相似文献
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