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

• Published in: International journal of hematology Vol. 92; no. 2; pp. 262 - 270
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Japan Springer Japan 01.09.2010; Springer; Springer Nature B.V
• Subjects: Apoptosis - immunology; Biological and medical sciences; Cell Line; Cell Proliferation; fas Receptor - immunology; fas Receptor - physiology; Hematologic and hematopoietic diseases; Hematology; Humans; Lymphocyte Activation; Medical sciences; Medicine; Medicine & Public Health; Oncology; Original Article; Protein Engineering; Recombinant Fusion Proteins; Signal Transduction - immunology; T-Lymphocytes - cytology; T-Lymphocytes - immunology; Fas; T cells; Activation signals; Apoptosis; Signal transduction; Hematology; Cell death; Intensity; T-Lymphocyte; Fas Antigen; Intracellular; Quantitative analysis
• ISSN: 0925-5710; 1865-3774
• DOI: 10.1007/s12185-010-0637-2

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, FLIP L and FLIP S , 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 FLIP L and FLIP S and the complete inhibition of FLIP S 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.