CD4+CD25+ Regulatory T Cells Resist a Novel Form of CD28- and Fas-Dependent p53-Induced T Cell Apoptosis

Singh, Nagendra; Yamamoto, Mutsumi; Takami, Mariko; Seki, Yoichi; Takezaki, Mayuko; Mellor, Andrew L.; Iwashima, Makio

doi:10.4049/jimmunol.0900753

Cited by 23 publications

(27 citation statements)

References 51 publications

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“…Thus, a plausible explanation for the lack of AICD in Tregs is diminished or absent CD95L expression. However, contradictory results regarding CD95L expression by Tregs have been obtained (16,(25)(26)(27)) that prompted us to investigate CD95L surface protein expression in Tregs compared with that in Tcons by a highly sensitive flow cytometry protocol. Tcons displayed high CD95L surface protein upon stimulation for 20 h with anti-CD3 Ab on day 6 of in vitro culture and upon P/I treatment on both day 0 (freshly isolated) and day 6 of culture ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Foxp3-Mediated Suppression of CD95L Expression Confers Resistance to Activation-Induced Cell Death in Regulatory T Cells

Weiß

Schmidt

Vobis

et al. 2011

The Journal of Immunology

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CD4+CD25++Foxp3+ regulatory T cells (Tregs) control self-reactive cells to maintain peripheral tolerance. Treg homeostasis has to be controlled tightly to ensure balanced Treg-mediated suppression. One mechanism that regulates the CD4+ T cell pool is activation-induced cell death (AICD). This is mimicked in vitro by TCR restimulation-induced expression of the death ligand CD95L (FasL/APO-1L/CD178) in expanded T cells. These cells express the death receptor CD95 (Fas/APO-1), and binding of CD95L to CD95 results in AICD. In contrast, Tregs do not undergo AICD upon TCR (re)stimulation in vitro despite a functional CD95 cell death pathway. In this study, we show that human and murine Tregs express low levels of CD95L upon stimulation. Knockdown of the transcriptional repressor Foxp3 partially rescues CD95L expression and AICD in human Tregs. Moreover, upon stimulation Foxp3-mutant Tregs from Scurfy mice express CD95L similar to conventional T cells. We further addressed whether exogenous CD95 stimulation provides a mechanism of Treg homeostatic control in vivo in mice. Triggering of CD95 reduced Treg numbers systemically as reflected by in vivo imaging and decreased GFP+ Treg numbers ex vivo. Our study reveals that Foxp3 negatively regulates CD95L expression in Tregs and demonstrates that Tregs are susceptible to homeostatic control by CD95 stimulation.

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Section: Resultsmentioning

confidence: 99%

Foxp3-Mediated Suppression of CD95L Expression Confers Resistance to Activation-Induced Cell Death in Regulatory T Cells

Weiß

Schmidt

Vobis

et al. 2011

The Journal of Immunology

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“…This phenomenon appeared to be independent of p53, although consistently, p53-deficient mice activated T cells were equally sensitive to AIDC as control mice [84]. Singh et al (2010) [85] observed a non-classical process of antigen-induced T cell death in CD4+CD25− and CD8+ T cells by sustained T cell receptor (TCR) stimulation caused by plate-bound anti-CD3/anti-CD28 antibodies (Abs) which is dependent on p53. The last contributes to cell death of CD4+CD25− cells via upregulation of Fas.…”

Section: P53 In Inflammatory and Autoimmune Conditionsmentioning

confidence: 99%

“…The last contributes to cell death of CD4+CD25− cells via upregulation of Fas. Remarkably, naturally occurring FoxP3+ Treg were found resistant to this form of apoptosis undergoing significant expansion upon stimulation [85]. Watanabe et al (2014) [86,87] highlighted, still in a mouse model, that downmodulation of p53 following TCR signaling enforces antigen-specific CD4+ T cell responses while limiting bystander proliferation of non-specific T cells.…”

Section: P53 In Inflammatory and Autoimmune Conditionsmentioning

confidence: 99%

The Double Role of p53 in Cancer and Autoimmunity and Its Potential as Therapeutic Target

Fierabracci

Pellegrino

2016

IJMS

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p53 is a sequence-specific short-lived transcription factor expressed at low concentrations in various tissues while it is upregulated in damaged, tumoral or inflamed tissue. In normally proliferating cells, p53 protein levels and function are tightly controlled by main regulators, i.e., MDM2 (mouse double minute 2) and MDM4 proteins. p53 plays an important role due to its ability to mediate tumor suppression. In addition to its importance as a tumor suppressor, p53 coordinates diverse cellular responses to stress and damage and plays an emerging role in various physiological processes, including fertility, cell metabolism, mitochondrial respiration, autophagy, cell adhesion, stem cell maintenance and development. Interestingly, it has been recently implicated in the suppression of autoimmune and inflammatory diseases in both mice and humans. In this review based on current knowledge on the functional properties of p53 and its regulatory pathways, we discuss the potential utility of p53 reactivation from a therapeutic perspective in oncology and chronic inflammatory disorders leading to autoimmunity.

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“…The identification and functional characterization of other important subsets of T cells, namely Tregs, T H 17 and NKT cells, has renewed interest in susceptibility to apoptosis as a mechanism of skewing of the immune response. Mouse Tregs have been shown to be highly resistant to FasL-mediated apoptosis, whereas freshly isolated human Tregs were susceptible but became resistant upon stimulation (142)(143)(144)(145). The data on T H 17 cell resistance to apoptosis is relatively sparse.…”

Section: Resistance To Apoptosis Among T-cell Subsetsmentioning

confidence: 99%

Multiple Mechanisms of Immune Suppression by B Lymphocytes

Klinker

Lundy

2011

Mol Med

109

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Suppression of the immune system after the resolution of infection or inflammation is an important process that limits immunemediated pathogenesis and autoimmunity. Several mechanisms of immune suppression have received a great deal of attention in the past three decades. These include mechanisms related to suppressive cytokines, interleukin (IL)-10 and transforming growth factor (TGF)-β, produced by regulatory cells, and mechanisms related to apoptosis mediated by death ligands, Fas ligand (FasL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), expressed by killer or cytotoxic cells. Despite many lines of evidence supporting an important role for B lymphocytes as both regulatory and killer cells in many inflammatory settings, relatively little attention has been given to understanding the biology of these cells, their relative importance or their usefulness as therapeutic targets. This review is intended to give an overview of the major mechanisms of immunosuppression used by B lymphocytes during both normal and inflammatory contexts. The more recent discoveries of expression of granzyme B, programmed death 1 ligand 2 (PD-L2) and regulatory antibody production by B cells as well as the interactions of regulatory and killer B cells with regulatory T cells, natural killer T (NKT) cells and other cell populations are discussed. In addition, new evidence on the basis of independent characterizations of regulatory and killer CD5 + B cells point toward the concept of a multipotent suppressor B cell with seemingly high therapeutic potential.

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CD4+CD25+ Regulatory T Cells Resist a Novel Form of CD28- and Fas-Dependent p53-Induced T Cell Apoptosis

Cited by 23 publications

References 51 publications

Foxp3-Mediated Suppression of CD95L Expression Confers Resistance to Activation-Induced Cell Death in Regulatory T Cells

Foxp3-Mediated Suppression of CD95L Expression Confers Resistance to Activation-Induced Cell Death in Regulatory T Cells

The Double Role of p53 in Cancer and Autoimmunity and Its Potential as Therapeutic Target

Multiple Mechanisms of Immune Suppression by B Lymphocytes

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