IL-2 Overcomes the Unresponsiveness but Fails to Reverse the Regulatory Function of Antigen-Induced T Regulatory Cells

Anderson, Per; Sundstedt, Anette; Yazıcı, Zihni Açar; Minaee, Sophie; Woolf, Richard S.; Nicolson, Kirsty; Whitley, Nat; Li, Li; Li, Suling; Wraith, David C; Wang, Ping

doi:10.4049/jimmunol.174.8.5133-a

Cited by 9 publications

(33 citation statements)

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“…We have found that antigen persistence can impair TCR signaling resulting in hyporesponsiveness (24). This hyporesponsiveness is gradually induced during antigen persistence with reduction of NFkB and AP1 activation (2, 24).…”

Section: Impaired Tcr Signaling During Chronic Virus Infectionmentioning

confidence: 99%

“…This hyporesponsiveness is gradually induced during antigen persistence with reduction of NFkB and AP1 activation (2, 24). This characteristic phenotype of T-cell tolerance is similar to that observed in chronic HBV infection (25).…”

Section: Impaired Tcr Signaling During Chronic Virus Infectionmentioning

confidence: 99%

“…In contrast to acute infection, antigen-specific T cells from chronic infectious diseases fail to produce IL-2 and TNFα, but express the regulatory cytokine IL-10 (4–6). We have discovered that antigen-specific CD4 T cells gradually alter their cytokine profile in response to antigen persistence in vivo (24). Initial antigen stimulation effectively induces IL-2 production in antigen-specific CD4 T cells in vivo , while repeated exposure to the same antigen yields CD4 T cells that produce both IL-2 and IL-10 (24).…”

Section: Altered Cytokine Production In T Cellsmentioning

confidence: 99%

“…We have discovered that antigen-specific CD4 T cells gradually alter their cytokine profile in response to antigen persistence in vivo (24). Initial antigen stimulation effectively induces IL-2 production in antigen-specific CD4 T cells in vivo , while repeated exposure to the same antigen yields CD4 T cells that produce both IL-2 and IL-10 (24). Antigen persistence can finally switch off the expression of IL-2 in T cells, but these cells still produce high levels of IL-10 (24).…”

Section: Altered Cytokine Production In T Cellsmentioning

confidence: 99%

“…Initial antigen stimulation effectively induces IL-2 production in antigen-specific CD4 T cells in vivo , while repeated exposure to the same antigen yields CD4 T cells that produce both IL-2 and IL-10 (24). Antigen persistence can finally switch off the expression of IL-2 in T cells, but these cells still produce high levels of IL-10 (24). This altered cytokine profile is associated with impaired proliferative responses and reduced AP1 and NFκB activation in response to antigen stimulation in vivo (24).…”

Section: Altered Cytokine Production In T Cellsmentioning

confidence: 99%

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Modulation of Antigen-Specific T-Cells as Immune Therapy for Chronic Infectious Diseases and Cancer

Symonds

Miao

et al. 2014

Front. Immunol.

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T-cell responses are induced by antigen presenting cells (APC) and signals from the microenvironment. Antigen persistence and inflammatory microenvironments in chronic infections and cancer can induce a tolerant state in T-cells resulting in hyporesponsiveness, loss of effector function, and weak biochemical signaling patterns in response to antigen stimulation. Although the mechanisms of T-cell tolerance induced in chronic infection and cancer may differ from those involved in tolerance to self-antigen, the impaired proliferation and production of IL-2 in response to antigen stimulation are hallmarks of all tolerant T cells. In this review, we will summarize the evidence that the immune responses change from non-self to “self”-like in chronic infection and cancer, and will provide an overview of strategies for re-balancing the immune response of antigen-specific T cells in chronic infection and cancer without affecting the homeostasis of the immune system.

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Section: Impaired Tcr Signaling During Chronic Virus Infectionmentioning

confidence: 99%

Section: Impaired Tcr Signaling During Chronic Virus Infectionmentioning

confidence: 99%

Section: Altered Cytokine Production In T Cellsmentioning

confidence: 99%

Section: Altered Cytokine Production In T Cellsmentioning

confidence: 99%

Section: Altered Cytokine Production In T Cellsmentioning

confidence: 99%

See 3 more Smart Citations

Modulation of Antigen-Specific T-Cells as Immune Therapy for Chronic Infectious Diseases and Cancer

Symonds

Miao

et al. 2014

Front. Immunol.

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Persistent antigenic stimulation alters the transcription program in T cells, resulting in antigen‐specific tolerance

et al. 2006

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Repetitive antigen stimulation induces peripheral T cell tolerance in vivo. It is not known, however, whether multiple stimulations merely suppress T cell activation or, alternatively, change the transcriptional program to a distinct, tolerant state. In this study, we have discovered that STAT3 and STAT5 were activated in response to antigen stimulation in vivo, in marked contrast to the suppression of AP-1, NF-jB and NFAT. In addition, a number of transcription factors were induced in tolerant T cells following antigen challenge in vivo, including T-bet, Irf-1 and Egr-2. The altered transcription program in tolerant cells associates closely with the suppression of cell cycle progression and IL-2 production, as well as with the induction of IL-10. Studies of T-bet and Egr-2 show that the function of T-bet in peptide treatment-induced regulatory T cells is not associated with Th1 differentiation, but correlates with the suppression of IL-2, whereas expression of Egr-2 led to an up-regulation of the cell cycle inhibitors p21 cip1 and p27 kip . Our results demonstrate a balanced transcription program regulated by different transcription factors for T cell activation and/or tolerance during antigen-induced T cell responses. Persistent antigen stimulation can induce T cell tolerance by changing the balance of transcription factors.See accompanying commentary http://www.dx

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The hidden truth about gene expression in Tregs: Is it what you don't see that counts?

Cobbold

2006

Eur J Immunol

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A population of IL‐10 secreting regulatory T cells (PI‐Tregs) can be induced in a mouse TCR transgenic model of experimental autoimmune encephalomyelitis (EAE) by intranasal administration of the N‐terminal peptide of myelin basic protein. A paper in this issue of the European Journal of Immunology identifies patterns of gene expression that distinguish PI‐Treg from naïve T cells after activation in vivo. PI‐Tregs are anergic and the expression of egr2 may be involved in regulation of the cell cycle. The surprising expression of the Th1 determining gene T‐bet in PI‐Tregs may be functionally relevant as transfection of T‐bet into a hybridoma induced some genes associated with regulatory T cells, such as tlr2 and gzmb. In this commentary, PI‐Tregs are considered in comparison to other Tregs, such as the natural CD4+CD25+ and Tr1 cells, and there seems to be considerable overlap in gene expression between all three Treg populations, but also with both Th1 and Th2 cells. It is suggested that regulatory activity may be a common feature of all activated T cells and that a defining principle of a Treg is the lack of effector functions due to a partial or incomplete differentiation to either Th1 or Th2. See accompanying article

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IL-2 Overcomes the Unresponsiveness but Fails to Reverse the Regulatory Function of Antigen-Induced T Regulatory Cells

Cited by 9 publications

References 0 publications

Modulation of Antigen-Specific T-Cells as Immune Therapy for Chronic Infectious Diseases and Cancer

Modulation of Antigen-Specific T-Cells as Immune Therapy for Chronic Infectious Diseases and Cancer

Persistent antigenic stimulation alters the transcription program in T cells, resulting in antigen‐specific tolerance

The hidden truth about gene expression in Tregs: Is it what you don't see that counts?

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