International Journal of Hematology

DOI: 10.1007/s12185-010-0637-2 Pages: 262-270

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

1. Yonsei University, Department of Biotechnology, College of Life Science and Biotechnology

2. Harvard University, School of Public Health, Department of Immunology and Infectious Diseases

3. Yale University School of Medicine, Department of Immunology

4. Korea Advanced Institute of Science and Technology, Graduate School of Medical Science and Engineering

5. Tokyo Medical and Dental University, School of Medicine, Department of Pediatrics

6. Yonsei University College of Medicine, Department of Microbiology

7. University of Ulsan, Department of Anatomy and Cell Biology, College of Medicine

Correspondence to:
Sang-Kyou Lee
Tel: +82-2-21232889
Fax: +82-2-3627265



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.

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