Qualitative and quantitative differences in the intensity of Fas-mediated intracellular signals determine life and death in T cells

Min Jung Shin, Jae Hyuck Shim, Jae Young Lee, Wook Jin Chae, Heung Kyu Lee, Tomohiro Morio, Jun Han Park, Eun Ju Chang, Sang Kyou Lee

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Fas stimulation has been reported to promote the activation and proliferation of T lymphocytes, but the intracellular signalling pathways that mediate non-apoptotic responses to Fas are poorly defined. To distinguish between the activation signalling and the death-inducing pathway downstream of Fas, we generated a novel T cell line expressing a chimeric hCD8-FasC protein and found that stimulation with the anti-CD8 antibodies induced tyrosine phosphorylation of TCR-proximal proteins, activation of Raf-1/ERK, p38 and JNK, and increased expression of CD69, Fas, and Fas ligand. Stimulation of hCD8-FasC-induced activation of an atypical NF-κB pathway, partial cleavage of caspases, and increased expression of TRAF1, FLIPL and FLIPS, thereby protecting T cells from FasL-mediated apoptosis. The proliferative response transmitted through hCD8-FasC chimeric receptors was converted into death signals when cells were stimulated, resulting in increased expression of IL-2 and Nur77 and increased caspase cleavage. Surprisingly, both the enhanced expression of FLIPL and FLIPS and the complete inhibition of FLIPS expression were functionally associated with cell death induction. These findings imply that Fas is able to trigger intracellular signalling events driving both apoptosis and activation of T cells but that cell fate is determined by quantitative and qualitative differences in intracellular signalling following Fas stimulation.

Original languageEnglish
Pages (from-to)262-270
Number of pages9
JournalInternational Journal of Hematology
Volume92
Issue number2
DOIs
Publication statusPublished - 2010 Sep 1

Fingerprint

T-Lymphocytes
Caspases
TNF Receptor-Associated Factor 1
Apoptosis
Fas Ligand Protein
Interleukin-2
Tyrosine
Anti-Idiotypic Antibodies
Proteins
Cell Death
Phosphorylation
Cell Line

All Science Journal Classification (ASJC) codes

  • Hematology

Cite this

Shin, Min Jung ; Shim, Jae Hyuck ; Lee, Jae Young ; Chae, Wook Jin ; Lee, Heung Kyu ; Morio, Tomohiro ; Park, Jun Han ; Chang, Eun Ju ; Lee, Sang Kyou. / Qualitative and quantitative differences in the intensity of Fas-mediated intracellular signals determine life and death in T cells. In: International Journal of Hematology. 2010 ; Vol. 92, No. 2. pp. 262-270.
@article{106303a7b5304324a2270aad1a93aac5,
title = "Qualitative and quantitative differences in the intensity of Fas-mediated intracellular signals determine life and death in T cells",
abstract = "Fas stimulation has been reported to promote the activation and proliferation of T lymphocytes, but the intracellular signalling pathways that mediate non-apoptotic responses to Fas are poorly defined. To distinguish between the activation signalling and the death-inducing pathway downstream of Fas, we generated a novel T cell line expressing a chimeric hCD8-FasC protein and found that stimulation with the anti-CD8 antibodies induced tyrosine phosphorylation of TCR-proximal proteins, activation of Raf-1/ERK, p38 and JNK, and increased expression of CD69, Fas, and Fas ligand. Stimulation of hCD8-FasC-induced activation of an atypical NF-κB pathway, partial cleavage of caspases, and increased expression of TRAF1, FLIPL and FLIPS, thereby protecting T cells from FasL-mediated apoptosis. The proliferative response transmitted through hCD8-FasC chimeric receptors was converted into death signals when cells were stimulated, resulting in increased expression of IL-2 and Nur77 and increased caspase cleavage. Surprisingly, both the enhanced expression of FLIPL and FLIPS and the complete inhibition of FLIPS expression were functionally associated with cell death induction. These findings imply that Fas is able to trigger intracellular signalling events driving both apoptosis and activation of T cells but that cell fate is determined by quantitative and qualitative differences in intracellular signalling following Fas stimulation.",
author = "Shin, {Min Jung} and Shim, {Jae Hyuck} and Lee, {Jae Young} and Chae, {Wook Jin} and Lee, {Heung Kyu} and Tomohiro Morio and Park, {Jun Han} and Chang, {Eun Ju} and Lee, {Sang Kyou}",
year = "2010",
month = "9",
day = "1",
doi = "10.1007/s12185-010-0637-2",
language = "English",
volume = "92",
pages = "262--270",
journal = "International Journal of Hematology",
issn = "0925-5710",
publisher = "Springer Japan",
number = "2",

}

Qualitative and quantitative differences in the intensity of Fas-mediated intracellular signals determine life and death in T cells. / Shin, Min Jung; Shim, Jae Hyuck; Lee, Jae Young; Chae, Wook Jin; Lee, Heung Kyu; Morio, Tomohiro; Park, Jun Han; Chang, Eun Ju; Lee, Sang Kyou.

In: International Journal of Hematology, Vol. 92, No. 2, 01.09.2010, p. 262-270.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Qualitative and quantitative differences in the intensity of Fas-mediated intracellular signals determine life and death in T cells

AU - Shin, Min Jung

AU - Shim, Jae Hyuck

AU - Lee, Jae Young

AU - Chae, Wook Jin

AU - Lee, Heung Kyu

AU - Morio, Tomohiro

AU - Park, Jun Han

AU - Chang, Eun Ju

AU - Lee, Sang Kyou

PY - 2010/9/1

Y1 - 2010/9/1

N2 - Fas stimulation has been reported to promote the activation and proliferation of T lymphocytes, but the intracellular signalling pathways that mediate non-apoptotic responses to Fas are poorly defined. To distinguish between the activation signalling and the death-inducing pathway downstream of Fas, we generated a novel T cell line expressing a chimeric hCD8-FasC protein and found that stimulation with the anti-CD8 antibodies induced tyrosine phosphorylation of TCR-proximal proteins, activation of Raf-1/ERK, p38 and JNK, and increased expression of CD69, Fas, and Fas ligand. Stimulation of hCD8-FasC-induced activation of an atypical NF-κB pathway, partial cleavage of caspases, and increased expression of TRAF1, FLIPL and FLIPS, thereby protecting T cells from FasL-mediated apoptosis. The proliferative response transmitted through hCD8-FasC chimeric receptors was converted into death signals when cells were stimulated, resulting in increased expression of IL-2 and Nur77 and increased caspase cleavage. Surprisingly, both the enhanced expression of FLIPL and FLIPS and the complete inhibition of FLIPS expression were functionally associated with cell death induction. These findings imply that Fas is able to trigger intracellular signalling events driving both apoptosis and activation of T cells but that cell fate is determined by quantitative and qualitative differences in intracellular signalling following Fas stimulation.

AB - Fas stimulation has been reported to promote the activation and proliferation of T lymphocytes, but the intracellular signalling pathways that mediate non-apoptotic responses to Fas are poorly defined. To distinguish between the activation signalling and the death-inducing pathway downstream of Fas, we generated a novel T cell line expressing a chimeric hCD8-FasC protein and found that stimulation with the anti-CD8 antibodies induced tyrosine phosphorylation of TCR-proximal proteins, activation of Raf-1/ERK, p38 and JNK, and increased expression of CD69, Fas, and Fas ligand. Stimulation of hCD8-FasC-induced activation of an atypical NF-κB pathway, partial cleavage of caspases, and increased expression of TRAF1, FLIPL and FLIPS, thereby protecting T cells from FasL-mediated apoptosis. The proliferative response transmitted through hCD8-FasC chimeric receptors was converted into death signals when cells were stimulated, resulting in increased expression of IL-2 and Nur77 and increased caspase cleavage. Surprisingly, both the enhanced expression of FLIPL and FLIPS and the complete inhibition of FLIPS expression were functionally associated with cell death induction. These findings imply that Fas is able to trigger intracellular signalling events driving both apoptosis and activation of T cells but that cell fate is determined by quantitative and qualitative differences in intracellular signalling following Fas stimulation.

UR - http://www.scopus.com/inward/record.url?scp=77956909856&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77956909856&partnerID=8YFLogxK

U2 - 10.1007/s12185-010-0637-2

DO - 10.1007/s12185-010-0637-2

M3 - Article

C2 - 20658220

AN - SCOPUS:77956909856

VL - 92

SP - 262

EP - 270

JO - International Journal of Hematology

JF - International Journal of Hematology

SN - 0925-5710

IS - 2

ER -