Molecular Antagonism and Plasticity of Regulatory and Inflammatory T Cell Programs

Yang, Xuexian O.; Nurieva, Roza; Martínez, Gustavo; Kang, Hong Soon; Chung, Yeonseok; Pappu, Bhanu P.; Shah, Bhavin; Chang, Seon Hee; Schluns, Kimberly S.; Watowich, Stephanie S.; Feng, Xin; Jetten, Anton M.; Dong, Chen

doi:10.1016/j.immuni.2008.05.007

Cited by 1,015 publications

(1,071 citation statements)

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“…Owing to FOXP3 instability or changes in its epigenetic control, Treg can lose FOXP3 expression and consequently immune suppressive activity (Wan and Flavell, 2007), thus demonstrating the plasticity of the FOXP3 program. In particular, inflammatory condition, with the presence of high amounts of IL-6, fully converts differentiated Foxp3 þ Treg cell into Th17 cells (Xu et al, 2007;Yang et al, 2008). This event is due to the capacity of STAT3 to downregulate the expression of FOXP3.…”

Section: Regulation Of Foxp3 Expressionmentioning

confidence: 99%

Human FOXP3 and cancer

et al. 2010

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FOXP3 is a transcription factor necessary and sufficient for induction of the immunosuppressive functions in regulatory T lymphocytes. Its expression was first considered as specific of this cell type, but FOXP3 can also be transiently expressed in T-cell antigen receptoractivated human nonregulatory T cells. Recent data indicate that FOXP3 is also expressed by some nonlymphoid cells, in which it can repress various oncogenes that are restored following FOXP3 deletion or mutation. This review summarizes major advances in (1) the understanding of Foxp3 functions in human regulatory T cells, (2) the prognostic significance of Foxp3-expressing T cells in human malignancies and (3) the significance of Foxp3 expression in human tumor cells.

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Section: Regulation Of Foxp3 Expressionmentioning

confidence: 99%

Human FOXP3 and cancer

et al. 2010

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“…Autoantigen-specific natural Treg are expanded in the peripheral lymphoid compartment after MOG immunization and are targeted to the CNS during EAE, resulting in in situ accumulation [9]. Naive T cells develop reciprocally into Treg or pathogenic Th17 cells, depending on the presence or absence of IL-6 in the local cytokine milieu [17][18][19]. The inflammatory environment not only controls T-cell differentiation but also affects Treg suppressor function in the target tissue [9].…”

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confidence: 99%

“…Naive T cells develop reciprocally into Treg or pathogenic Th17 cells, depending on the presence or absence of IL-6 in the local cytokine milieu [17][18][19]. The inflammatory environment not only controls T-cell differentiation but also affects Treg suppressor function in the target tissue [9].CCR6 is a common marker of certain tissue-homing Treg [15,16] and Th17 cells [20]; these two cell types show a clear functional dichotomy in inflammatory processes, and both are directly involved in autoimmune disease regulation [18,19]. EAE is thus an excellent model for analysis of the CD4/Th1/Th17/ Treg pathway, and CCR6 À/À mice are useful for determining the function of this receptor in in vivo EAE development.…”

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confidence: 99%

“…CCR6 is a common marker of certain tissue-homing Treg [15,16] and Th17 cells [20]; these two cell types show a clear functional dichotomy in inflammatory processes, and both are directly involved in autoimmune disease regulation [18,19]. EAE is thus an excellent model for analysis of the CD4/Th1/Th17/ Treg pathway, and CCR6 À/À mice are useful for determining the function of this receptor in in vivo EAE development.…”

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confidence: 99%

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CCR6 regulates EAE pathogenesis by controlling regulatory CD4⁺ T‐cell recruitment to target tissues

et al. 2009

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The T-cell subsets, characterized by their cytokine production profiles and immune regulatory functions, depend on correct in vivo location to interact with accessory or target cells for effective immune responses. Differentiation of naive CD4 1 T cells into effectors is accompanied by sequentially regulated expression of the chemokine receptors responsible for cell recruitment to specific tissues. We studied CCR6 function in EAE, a CD4 1 T-cell-mediated CNS disease characterized by mononuclear infiltration and demyelination. CCR6 À/À mice showed an altered time course of EAE development, with delayed onset, a higher clinical score, and more persistent symptoms than in controls. An imbalanced cytokine profile and reduced Foxp3 1 cell frequency characterized CNS tissues from CCR6 À/À compared with CCR6 1/1 mice during the disease effector phase. Transfer of CCR6 1/1 Treg to CCR6 À/À mice the day before EAE induction reduced the clinical score associated with an increased in infiltrating Foxp3 1 cells and recovery of the cytokine balance in CCR6 À/À mouse CNS. Competitive assays between CCR6 1/1 and CCR6 À/À Treg adoptively transferred to CCR6 À/À mice showed impaired ability of CCR6 À/À Treg to infiltrate CNS tissues in EAE-affected mice. Our data indicate a CCR6 requirement by CD4 1 Treg to downregulate the CNS inflammatory process and neurological signs associated with EAE.Key words: Chemokines . EAE/MS . Inflammation . T cells Introduction EAE is a CNS disease characterized by mononuclear cell infiltration and demyelination; it is used to study certain aspects of human MS. EAE can be induced via immunization with neural antigens such as myelin oligodendrocyte glycoprotein (MOG). The immunopathological event in EAE and MS initiates when autoreactive T cells in the systemic immune compartment are activated and cross the blood-brain barrier [1]. Re-encounter of encephalitogenic T cells with their antigen leads to reactivation and expansion of autoreactive T cells, which in turn stimulate microglia/astrocyte activity, with increased release of proinflammatory cytokines and chemokines. The action of these mediators leads to demyelination and axon degeneration [2,3]. After antigen contact, naive CD4 1 T cells differentiate into various effector-cell subsets characterized by the cytokines they produce and by their immune regulatory functions. Th1 and Th17 cytokine profile effector cells and antigen-specific Treg have a critical role in EAE pathogenesis [4][5][6][7][8][9][10]. In MOG-induced EAE, both antigen-specific T-effector and Treg differentiate and proliferate in the periphery before migrating to the CNS [9]. Differentiation is accompanied by sequential expression of selectins, integrins, and chemokine receptors responsible for T-cell-subset recruitment to and extravasation at inflammation sites. The correct in vivo location of these cell subsets, necessary for their interaction with accessory or target cells, is regulated by [11], which are assumed to have a critical impact on MS and EAE pathogenesis [12]. St...

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“…Nevertheless, a common developmental origin between human Th17 and Th1 cells has been described in various studies [4][5][6]. Accordingly, human Th17 clones appear to express IL-12Rβ2 in addition to IL-23R, and the transcription factor Tbet in addition to RORγt, as well a remarkable proportion of human Th17 cells, produces both IL-17A and IFN-γ, or human Th17 clones can be induced to produce IFN-γ and upregulate T-bet expression when cultured in the presence of IL-12 [7]. This close relationship between Th1 and Th17 cells is also marked in their capacity to cause T-cell-mediated inflammation and autoimmune disease.…”

Section: Introductionmentioning

confidence: 97%

Th17 cells in systemic lupus erythematosus share functional features with Th17 cells from normal bone marrow and peripheral tissues

et al. 2011

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This study was designed to investigate the functional heterogeneity of human Th17 and how their plasticity shapes the nature of immune cell responses to inflammation and autoimmune diseases, such as systemic lupus erythematosus (SLE). We evaluated functional Th17 cell subsets based on the profile of cytokine production in peripheral blood (PB), bone marrow aspirates (BM) and lymph node biopsies (LN) from healthy individuals (n=35) and PB from SLE patients (n=34). Data were analysed by an automated method for merging and calculation of flow cytometric data, allowing us to identify eight Th17 subpopulations. Normal BM presented lower frequencies of Th17 (p=0.006 and p=0.05) and lower amount of IL-17 per cell (p=0.03 and p=0.02), compared to normal PB and LN biopsies. In the latter tissues were found increased proportions of Th17 producing TNF-α or TNF-α/IL-2 or IFN-γ/TNF-α/IL-2, while in BM, Th17 producing other cytokines than IL-17 was clearly decreased. In SLE patients, the frequency of Th17 was higher than in control, but the levels of IL-17 per cell were significantly reduced (p<0.05). Among the eight generated subpopulations, despite the great functional heterogeneity of Th17 in SLE, a significant low proportion of Th17 producing TNF-α was found in inactive SLE, while active SLE showed a high proportion producing only IL-17. Our findings support the idea that the functional heterogeneity of Th17 cells could depend on the cytokine microenvironment, which is distinct in normal BM as well as in active SLE, probably due to a Th1/Th2 imbalance previously reported by our group.

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Molecular Antagonism and Plasticity of Regulatory and Inflammatory T Cell Programs

Cited by 1,015 publications

References 28 publications

Human FOXP3 and cancer

Human FOXP3 and cancer

CCR6 regulates EAE pathogenesis by controlling regulatory CD4⁺ T‐cell recruitment to target tissues

Th17 cells in systemic lupus erythematosus share functional features with Th17 cells from normal bone marrow and peripheral tissues

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Molecular Antagonism and Plasticity of Regulatory and Inflammatory T Cell Programs

Cited by 1,015 publications

References 28 publications

Human FOXP3 and cancer

Human FOXP3 and cancer

CCR6 regulates EAE pathogenesis by controlling regulatory CD4+ T‐cell recruitment to target tissues

Th17 cells in systemic lupus erythematosus share functional features with Th17 cells from normal bone marrow and peripheral tissues

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CCR6 regulates EAE pathogenesis by controlling regulatory CD4⁺ T‐cell recruitment to target tissues