Tumor Immunity in Perforin-Deficient Mice: A Role for CD95 (Fas/APO-1)

Rosen, Dalia; Li, Jie-Hui; Keidar, Sergey; Markon, Ilya; Orda, Ruben; Berke, Gideon

doi:10.4049/jimmunol.164.6.3229

Cited by 57 publications

(41 citation statements)

References 36 publications

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“…Thus, reduced sensitivity to CD95-mediated apoptosis signals can conceivably lead to escape of virusinfected cells from immune surveillance. [17][18][19][20][21][22] Here we have found elevated levels of HGF and EGF in HBVinfected individuals and show that these growth factors stimulate survival signaling in primary human hepatocytes. Our findings support the notion that survival programs induced by EGF/HGF signaling may contribute to an apoptosis resistant phenotype in hepatocytes in the infected liver, thus contributing to immune escape and persistence of the viral infection.…”

mentioning

confidence: 55%

EGF and HGF levels are increased during active HBV infection and enhance survival signaling through extracellular matrix interactions in primary human hepatocytes

Barreiros

Sprinzl

Rosset

et al. 2008

Intl Journal of Cancer

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The hepatitis B virus (HBV) is a major causative agent of chronic liver disease and subsequent liver cirrhosis worldwide. The reduced sensitivity of virus-infected liver cells to apoptosis may play a role in the failure to remove virus-infected cells and eventually promote viral chronicity. The purpose of our study was to investigate whether survival factors induced during compensatory liver regeneration may protect hepatocytes against apoptosis. We evaluated the serum levels of hepatocyte growth factor (HGF) and epidermal growth factor (EGF) in HBV-infected patients and found significant increases in HGF and EGF in patients with active virus infection. In primary human hepatocytes we show that HGF and EGF have a protective effect against CD95-mediated apoptosis and cytotoxic T-cell killing. Simultaneous treatment with both regeneration factors enhanced the cytoprotective effect. The PI 3-K/Akt kinase inhibitor, wortmannin, and the STAT3 pathway inhibitor, Tyrphostin AG490, both effectively attenuated the cytoprotective effect of HGF and EGF. Furthermore, we show an EGF/HGF-dependent upregulation of b 1 -integrin chains, increased adhesion to extracellular matrix and an increase in focal adhesions, suggesting outside-in signaling from the extracellular matrix as an additional cytoprotective mechanism. Our study demonstrates that HGF and EGF can interfere with CD95-mediated apoptosis and the action of cytotoxic T-cells through multiple mechanisms in human hepatocytes. Together our results argue that a survival mileau generated by activation of liver regeneration factors may be a risk factor for establishing viral persistence.

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mentioning

confidence: 55%

EGF and HGF levels are increased during active HBV infection and enhance survival signaling through extracellular matrix interactions in primary human hepatocytes

Barreiros

Sprinzl

Rosset

et al. 2008

Intl Journal of Cancer

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“…Moreover, tumor cells became sensitive to CD95-mediated apoptosis during in vivo passage, most likely through up-regulation of CD95, as has also been observed by others using the same parental cell line (LF -) [39]. Hence, an analysis of the influence of CD95L expression on anti-tumor T cells was not possible in anti-K b TCR-transgenic perforin -/-mice.…”

Section: Discussionmentioning

confidence: 80%

The influence of CD95L expression on tumor rejection in mice

Igney¹,

Behrens²,

Krammer³

2003

Eur J Immunol

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Many tumors express the death ligand CD95L (CD178, APO-1L, FasL) and can kill activated T cells in vitro. This may enable the tumor cells to suppress anti-tumor immune responses, a phenomenon called "tumor counterattack". Preliminary evidence of tumor counterattack in human tumors exists. However, CD95L-expressing tumors are rapidly rejected in mice. In order to clarify this controversial situation we investigated whether the level or the time point of CD95L expression might be critical factors determining tumor counterattack versus tumor rejection. We generated CD95-resistant tumor cell lines expressing different levels of CD95L (LKC-CD95L). In nude mice the CD95L expression level had no influence on the growth of the CD95L + tumors. In contrast, a CD95L -control tumor cell line (LKC) grew much faster. In addition, we generated a CD95-resistant cell line in which CD95L was induced via the tet system (LKCR-tetCD95L). Induction of CD95L in established tumors in nude and NOD/SCID mice led to rapid rejection of the tumors. Induction of lower CD95L expression levels delayed tumor rejection only marginally. These results demonstrate that rejection of CD95L-expressing tumors in mice is not a result of overexpression and does not depend on the presence of CD95L at the onset of tumor progression.

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“…Alloreactive peritoneal exudate lymphocytes (PELs) were produced in 6-to 10-week-old mice, purified and tested for their cytotoxic activity by the 51 Cr-release assay as described (36). For monitoring CD8 ϩ T cell proliferation, cells were liberated from spleen and RBC removed by treatment with ACK buffer (0.15 M NH 4 Cl͞1 mM KHCO 3 ͞ 0.1 mM Na 2 EDTA).…”

Section: Methodsmentioning

confidence: 99%

Runx3 and Runx1 are required for CD8 T cell development during thymopoiesis

Woolf

Xiao

Fainaru

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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348

356

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The RUNX transcription factors are important regulators of lineagespecific gene expression. RUNX are bifunctional, acting both as activators and repressors of tissue-specific target genes. Recently, we have demonstrated that Runx3 is a neurogenic transcription factor, which regulates development and survival of proprioceptive neurons in dorsal root ganglia. Here we report that Runx3 and Runx1 are highly expressed in thymic medulla and cortex, respectively, and function in development of CD8 T cells during thymopoiesis. Runx3-deficient (Runx3 KO) mice display abnormalities in CD4 expression during lineage decisions and impairment of CD8 T cell maturation in the thymus. A large proportion of Runx3 KO peripheral CD8 T cells also expressed CD4, and in contrast to wild-type, their proliferation ability was largely reduced. In addition, the in vitro cytotoxic activity of alloimmunized peritoneal exudate lymphocytes was significantly lower in Runx3 KO compared with WT mice. In a compound mutant mouse, null for Runx3 and heterozygous for Runx1 (Runx3 ؊/؊ ;Runx1 ؉/؊ ), all peripheral CD8 T cells also expressed CD4, resulting in a complete lack of single-positive CD8 ؉ T cells in the spleen. The results provide information on the role of Runx3 and Runx1 in thymopoiesis and suggest that both act as transcriptional repressors of CD4 expression during T cell lineage decisions.T he mammalian RUNX3͞AML2 gene resides on human chromosome 1p36.1 and mouse chromosome 4, respectively (1-4). It belongs to the RUNX family of transcription factors, which contains three genes. The two other family members, RUNX1 and RUNX2, play fundamental roles in hematopoietic and osteogenic lineage-specific gene expression, and when mutated, are associated with human diseases (5, 6). The three RUNX genes are regulated at the transcriptional level by two promoters, and at the translational level by internal ribosome entry site (IRES)-and cap-dependent translation control (7-14). The gene products of RUNX bind to the same DNA motif and activate or repress transcription of target genes through recruitment of common transcriptional modulators (15)(16)(17)(18). Despite this occurrence, each of the Runx genes has well defined biological functions reflected in a different expression pattern of the genes (19-23) and distinct phenotypes of the corresponding knockout mice (6,(24)(25)(26)(27).During mouse embryogenesis Runx3 is expressed in hematopoietic organs, epidermal appendages, developing bones, and sensory ganglia (20). Studies in knockout (KO) mice revealed that Runx3 is a neurogenic-specific transcription factor required for development and survival of TrkC neurons in the dorsal root ganglia. In the absence of Runx3 these neurons die, leading to disruption of the stretch reflex neuronal circuit, and consequently to severe ataxia (25,26). Intriguingly, in one strain of Runx3 KO, the gastric mucosa of newborn mice exhibits hyperplasia due to stimulated proliferation and suppressed apoptosis of stomach epithelial cells (27).It has previously been reporte...

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Tumor Immunity in Perforin-Deficient Mice: A Role for CD95 (Fas/APO-1)

Cited by 57 publications

References 36 publications

EGF and HGF levels are increased during active HBV infection and enhance survival signaling through extracellular matrix interactions in primary human hepatocytes

EGF and HGF levels are increased during active HBV infection and enhance survival signaling through extracellular matrix interactions in primary human hepatocytes

The influence of CD95L expression on tumor rejection in mice

Runx3 and Runx1 are required for CD8 T cell development during thymopoiesis

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