Transgenic overexpression of the Caspase‐8 inhibitor FLIP<sub>short</sub> leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection

Oehme, Ina; Neumann, Frank; Bösser, Susanne; Zörnig, Martin

doi:10.1002/eji.200425564

Cited by 17 publications

(25 citation statements)

References 47 publications

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“…Interestingly, the increased proliferation of FasL ⌬Intra T cells is reduced to wild-type levels in the presence of inhibitory CD4 ϩ CD25 ϩ regulatory T cells, 34 which indicates that additional control mechanisms act in vivo. As we did not find obvious differences in the in vivo proliferation of V␤8 ϩ T cells following injection of wild-type and FasL ⌬Intra mice with the superantigen SEB, our data substantiates the notion that regulatory T cells display an inhibitory influence on the increased activation-induced proliferation of FasL ⌬Intra T cells (Oehme et al 35 and data not shown). An alternative explanation for the SEB result builds on the fact that according to several in vitro studies, the influence of FasL reverse signaling on T-cell proliferation is only observable under conditions of suboptimal stimulation.…”

Section: Discussionsupporting

confidence: 90%

Immune modulation by Fas ligand reverse signaling: lymphocyte proliferation is attenuated by the intracellular Fas ligand domain

Lückerath

Kirkin

Melzer

et al. 2011

Blood

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Fas ligand (FasL) not only induces apoptosis in Fas receptor-bearing target cells, it is also able to transmit signals into the FasL-expressing cell via its intracellular domain (ICD). IntroductionFas ligand (FasL, CD95L, CD178, TNSF6) is a 40-kDa glycosylated type II transmembrane protein that belongs to the tumor necrosis factor (TNF) family. Its extracellular portion harbors a C-terminal TNF homology domain that assembles as homotrimers and mediates interactions with receptors. Interestingly, the 77-amino acid (aa)-long N-terminal mouse FasL intracellular domain (ICD) contains several conserved signaling motifs, such as a tandem casein kinase I phosphorylation site (aa 17-21), a proline-rich domain (PRD; aa 45-69) that serves as a docking site for SH3 domain-containing proteins, and a tyrosine phosphorylation site located at aa 7. 1 The FasL/Fas receptor system is renowned as a potent inducer of apoptosis in the receptor-bearing cell and is especially important for numerous immune system functions, including removal of target cells by natural killer and cytotoxic T cells, (self) elimination of effector cells after the proliferative phase of an immune response (activation-induced cell death), and maintenance of immuneprivileged sites. 2,3 Naturally occurring homozygous mutations of the Fas (lpr) and the FasL (gld) genes, which abolish Fas-mediated apoptosis, lead to development of a severe lymphoproliferative disease. 4 Because of its potent proapoptotic potential and important function, expression and activity of FasL is tightly regulated at transcriptional and posttranslational levels and is restricted to a few cell types, such as immune effector cells and cells of immuneprivileged sites (eg, eyes, testis, brain). In contrast, the Fas receptor is expressed in a wide variety of tissues, including the lymphoid tissues, liver, heart, and ovary. 1,5 In addition to its pro-death function, the Fas/FasL system also transduces nonapoptotic signals into the Fas-expressing cells. Among others, Fas is required for cell survival, proliferation and activation of T cells, liver regeneration, and neurogenesis. 6,7 A number of studies have presented evidence for alternative signal transduction via "reverse signaling" into the FasL-bearing cells, although conflicting data have been published regarding the functional implications (for review see Voss et al 1 ). First evidence The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 8, 2018. by guest www.bloodjournal.org From for the existence of retrograde FasL signaling stems from 2 studies that demonstrated either costimulation of murine CD8 ϩ cytotoxic T lymphocyte (CTL) cell lines upon FasL cross-linking 8 or inhibition of activation-induced proliferation in murine CD4 ϩ T cells. 9 In both cases, FasL reverse signaling could...

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Section: Discussionsupporting

confidence: 90%

Immune modulation by Fas ligand reverse signaling: lymphocyte proliferation is attenuated by the intracellular Fas ligand domain

Lückerath

Kirkin

Melzer

et al. 2011

Blood

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“…By contrast, c-FLIPs (short form) and K13 v-FLIP Tg mice do not exhibit any abnormalities in thymic development (8,25). We found that thymic development as determined by the percentages of CD4 Ϫ 8 Ϫ DN, CD4 ϩ 8 ϩ DP, and CD4 Ϫ 8 ϩ or CD4 ϩ 8 Ϫ SP thymocytes and thymic cellularity was normal in the Tg mice (Fig.…”

Section: Normal Lymphocyte Development and Lymphoproliferation In Thementioning

confidence: 65%

Transgenic Expression of the Viral FLIP MC159 Causes lpr/gld-Like Lymphoproliferation and Autoimmunity

Woelfel

Bixby

Brehm

et al. 2006

The Journal of Immunology

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Death receptor-induced programmed cell death (PCD) is crucial for the maintenance of immune homeostasis. However, interference of downstream death receptor signaling by genetic ablation or transgenic (Tg) expression of different apoptosis inhibitors often impairs lymphocyte activation. The viral FLICE (caspase-8)-like inhibitor proteins (v-FLIPs) are potent inhibitors of death receptor-induced apoptosis and programmed necrosis. We generated Tg mice expressing the v-FLIP MC159 from Molluscum contagiosum virus under the control of the H2Kb class I MHC promoter to examine the role of death receptor-induced PCD in the control of immune functions and homeostasis. We found that expression of MC159 led to lymphoproliferation and autoimmunity as exemplified by T and B lymphocyte expansion, accumulation of TCRαβ+CD3+B220+CD4−CD8− lymphocytes in secondary lymphoid organs, elevated serum Ig levels, and increased anti-dsDNA Ab titers. These phenotypes were caused by defective death receptor-induced apoptosis, but not by defective passive cell death in the absence of mitogenic stimulation. Lymphocyte activation was normal, as demonstrated by normal thymidine incorporation and CSFE dilution of T cells stimulated with anti-CD3 and anti-CD28 Abs. In addition, effector CD8+ T cell responses to acute and memory lymphocytic choriomeningitis virus infections were unaffected in the Tg mice. These phenotypes are reminiscent of the lpr and gld mice, and show that the v-FLIP MC159 is a bona fide PCD inhibitor that does not interfere with other essential lymphocyte functions. Thus, the MC159-Tg mice provide a model to study the effects of PCD in immune responses without hampering other important lymphocyte functions.

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“…A previous study demonstrated that overexpression of c-FLIP S in T cells inhibited T cell proliferation (23). To rule out the possibility that the impaired CD8 ϩ effector T cell differentiation observed in c-FLIP L Ϫ/Ϫ mice was due to inhibition by the c-FLIP S BAC tg, we compared CD8 ϩ effector T cell development in c-FLIP f/f and c-FLIP f/f c-FLIP S BAC tg mice.…”

Section: Impaired Effector T Cell Development In C-flip L ϫ/ϫ Micementioning

confidence: 99%

The Long Isoform of Cellular FLIP Is Essential for T Lymphocyte Proliferation through an NF-κB-Independent Pathway

Zhang

Hopkins

2008

The Journal of Immunology

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Although the long isoform of cellular FLIP (c-FLIPL) has been implicated in TCR-mediated signaling, its role in T cell proliferation remains controversial. Some studies have demonstrated that overexpression of c-FLIPL promotes T cell proliferation and NF-κB activation, whereas others have reported that c-FLIPL overexpression has no effect or even inhibits T cell proliferation. To establish the role of c-FLIPL in T lymphocyte proliferation, we have generated a conditional knockout mouse strain specifically lacking c-FLIPL in T lymphocytes. c-FLIPL−/− mice exhibit severely impaired effector T cell development after Listeria monocytogenes infection in vivo and c-FLIPL-deficient T cells display defective TCR-mediated proliferation in vitro. However, c-FLIPL−/− T cells exhibit normal NF-κB activity upon TCR stimulation. These results demonstrate that c-FLIPL is essential for T lymphocyte proliferation through an NF-κB-independent pathway.

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Transgenic overexpression of the Caspase‐8 inhibitor FLIP_short leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection

Cited by 17 publications

References 47 publications

Immune modulation by Fas ligand reverse signaling: lymphocyte proliferation is attenuated by the intracellular Fas ligand domain

Immune modulation by Fas ligand reverse signaling: lymphocyte proliferation is attenuated by the intracellular Fas ligand domain

Transgenic Expression of the Viral FLIP MC159 Causes lpr/gld-Like Lymphoproliferation and Autoimmunity

The Long Isoform of Cellular FLIP Is Essential for T Lymphocyte Proliferation through an NF-κB-Independent Pathway

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Transgenic overexpression of the Caspase‐8 inhibitor FLIPshort leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection

Cited by 17 publications

References 47 publications

Immune modulation by Fas ligand reverse signaling: lymphocyte proliferation is attenuated by the intracellular Fas ligand domain

Immune modulation by Fas ligand reverse signaling: lymphocyte proliferation is attenuated by the intracellular Fas ligand domain

Transgenic Expression of the Viral FLIP MC159 Causes lpr/gld-Like Lymphoproliferation and Autoimmunity

The Long Isoform of Cellular FLIP Is Essential for T Lymphocyte Proliferation through an NF-κB-Independent Pathway

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Transgenic overexpression of the Caspase‐8 inhibitor FLIP_short leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection