Regulation of Foxp3+ Inducible Regulatory T Cell Stability by SOCS2

Knosp, Camille; Schiering, Chris; Spence, Shaun; Carroll, Helen P.; Nel, H J; Osbourn, Megan; Jackson, Ruaidhrí; Lyubomska, Oksana; Malissen, Bernard; Ingram, Rebecca J.; Fitzgerald, Denise; Powrie, Fiona; Fallon, Padraic G.; Johnston, James A.; Kissenpfennig, Adrien

doi:10.4049/jimmunol.1201396

Cited by 45 publications

(39 citation statements)

References 58 publications

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“…In addition to its roles in iTreg cell generation and proliferation, IL-2 signaling is important for iTreg cell stability in vivo (Chen et al, 2011). Also, expression of the suppressor of cytokine signaling-2 (SOCS2) protein plays a role in preventing IL-4-dependent iTreg instability (Knosp et al, 2013). In summary, a complex, regulated series of interactions with Foxp3 are required for the establishment of Treg cell stability.…”

Section: Stability Of Itreg Cellsmentioning

confidence: 99%

Generation and Function of Induced Regulatory T Cells

Schmitt¹,

Williams²

2013

Front. Immunol.

175

147

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CD4+ CD25+ Foxp3+ regulatory T (Treg) cells are essential to the balance between pro- and anti-inflammatory responses. There are two major subsets of Treg cells, “natural” Treg (nTreg) cells that develop in the thymus, and “induced” Treg (iTreg) cells that arise in the periphery from CD4+ Foxp3− conventional T cells and can be generated in vitro. Previous work has established that both subsets are required for immunological tolerance. Additionally, in vitro-derived iTreg cells can reestablish tolerance in situations where Treg cells are decreased or defective. This review will focus on iTreg cells, drawing comparisons to nTreg cells when possible. We discuss the molecular mechanisms of iTreg cell induction, both in vivo and in vitro, review the Foxp3-dependent and -independent transcriptional landscape of iTreg cells, and examine the proposed suppressive mechanisms utilized by each Treg cell subset. We also compare the T cell receptor repertoire of the Treg cell subsets, discuss inflammatory conditions where iTreg cells are generated or have been used for treatment, and address the issue of iTreg cell stability.

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Section: Stability Of Itreg Cellsmentioning

confidence: 99%

Generation and Function of Induced Regulatory T Cells

Schmitt¹,

Williams²

2013

Front. Immunol.

175

147

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“…In line with this idea, treatment of murine melanomas with a GITR agonistic antibody resulted in the accumulation of exT reg at the tumor site (164). Suppressor of cytokine signaling (SOCS) 1 and 2, which maintain Foxp3 stability and prevent T reg polarization into effector cells (165, 166), may be pharmacologically inhibited to unlock T reg responsiveness to pro-inflammatory microenvironmental cytokines.…”

Section: Implications For Cancer Immunotherapymentioning

confidence: 99%

Convergences and Divergences of Thymus- and Peripherally Derived Regulatory T Cells in Cancer

Burocchi¹,

Colombo²,

Piconese³

2013

Front. Immunol.

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The expansion of regulatory T cells (Treg) is a common event characterizing the vast majority of human and experimental tumors and it is now well established that Treg represent a crucial hurdle for a successful immunotherapy. Treg are currently classified, according to their origin, into thymus-derived Treg (tTreg) or peripherally induced Treg (pTreg) cells. Controversy exists over the prevalent mechanism accounting for Treg expansion in tumors, since both tTreg proliferation and de novo pTreg differentiation may occur. Since tTreg and pTreg are believed as preferentially self-specific or broadly directed to non-self and tumor-specific antigens, respectively, the balance between tTreg and pTreg accumulation may impact on the repertoire of antigen specificities recognized by Treg in tumors. The prevalence of tTreg or pTreg may also affect the outcome of immunotherapies based on tumor-antigen vaccination or Treg depletion. The mechanisms dictating pTreg induction or tTreg expansion/stability are a matter of intense investigation and the most recent results depict a complex landscape. Indeed, selected Treg subsets may display peculiar characteristics in terms of stability, suppressive function, and cytokine production, depending on microenvironmental signals. These features may be differentially distributed between pTreg and tTreg and may significantly affect the possibility of manipulating Treg in cancer therapy. We propose here that innovative immunotherapeutic strategies may be directed at diverting unstable/uncommitted Treg, mostly enriched in the pTreg pool, into tumor-specific effectors, while preserving systemic immune tolerance ensured by self-specific tTreg.

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“…Expression of SOCS2 is associated with positive prognosis in human breast cancer (23,24), but with malignancy in prostate (25) and colorectal (26) cancer. Its role in hematological malignancies is not yet clear, although SOCS2 is involved in T-cell differentiation (27), and stability (28). SOCS2 inhibits Janus kinase/signal transducer and activator of transcription signaling, but can also influence EGFR signaling.…”

Section: Localization Of Wnt1-inducible Signaling Pathway Protein 1mentioning

confidence: 99%

Differential Expression of Ccn4 and Other Genes Between Metastatic and Non-metastatic EL4 Mouse Lymphoma Cells

Chahal

Legaspi

et al. 2016

CGP

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EL4 is a murine lymphoma cell line developed in 1945 by treating C57 black mice with 9:10-dimethyl-1:2-benzanthracene (1). The cells were originally propagated in animal hosts, prior to adaptation to cell culture. EL4 cells were used for many years as a source of interleukin-2 (IL2), which they secrete when treated with phorbol 12-myristate 13-acetate (PMA).The EL4 cell line originally provided to us, by a colleague at the University of Washington, was heterogeneous with respect to PMA response. We, therefore, developed and characterized EL4 sub-lines. Wild-type (WT)-derived cell lines, which are PMA responsive, grow readily in suspension culture as did the original strain. Variant (V)-derived (PMA-resistant) sub-lines were selected for enhanced adhesion to tissue culture plastic (2). Clonal lines were developed from both cell types by limiting dilution (3). The PMA sensitivity of WT-derived cells, as reflected by PMA-induced IL2 production and mitogen-activated protein kinase (ERK1/2) activation, has been attributed to expression of Ras guanyl nucleotide releasing protein 1 (RasGRP1), which binds PMA and directly activates Ras (4); V-derived cells do not express RasGRP1.Clonal EL4 cell lines were used for experimental metastasis studies in syngeneic mice, with WT2 and V7 as prototypes (5, 6). WT2 cells do not form tumors (nonmetastatic), while V7 cells form liver tumors (metastatic) after tail vein injection. 'Metastasis' more strictly refers to tumorigenesis in this model, since circulating EL4 cells home to the liver to form tumors (5). The clonal C5 cell line was developed after stably overexpressing human hemagllutinin (HA)-tagged phospholipase D2 (PLD2) in V7 cells in order to characterize the signaling role of PLD2 using a cell line expressing little or no endogenous PLD2 (5). As compared to V7, C5 cells exhibit increased cell migration (7) and tumor growth (5), providing an early example of the positive role of PLD2 in tumorigenesis.This report presents data from microarray analyses comparing transcripts expressed by these three EL4 cell types, with the goal of further defining their phenotypes.

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Regulation of Foxp3+ Inducible Regulatory T Cell Stability by SOCS2

Cited by 45 publications

References 58 publications

Generation and Function of Induced Regulatory T Cells

Generation and Function of Induced Regulatory T Cells

Convergences and Divergences of Thymus- and Peripherally Derived Regulatory T Cells in Cancer

Differential Expression of Ccn4 and Other Genes Between Metastatic and Non-metastatic EL4 Mouse Lymphoma Cells

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