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Reverse signaling by FasL inhibits primary human T cell activation

The death-factor Fas Ligand (FasL) is best known for its capacity to induce cell death in Fas-expressing cells. Besides its death-promoting activity, FasL has been implicated in reverse signaling and might thus also play a role in T cell development and selection and the modulation of T cell activation by acting as a costimulatory receptor. Here we have analyzed the influence of FasL-costimulation on TCR/CD3/CD28-triggered activation of peripheral human T-lymphocytes. Interestingly, FasL engagement inhibited the proliferation of PBMC, CD8+ as well as CD4+ T cells. Plate-bound but not soluble FasFc fusion protein or anti-FasL pAb blocked CD3/CD28-induced proliferation almost completely. We observed not only less proliferation, but also decreased IL-2 production and reduced expression of the activation markers CD69 and CD25. Importantly, FasFc costimulation also resulted in a dramatic inhibition of TCR internalization, thereby preventing TCR translocation and the formation of signaling platforms essential for optimal T cell activation. Consistent with these findings, various crucial signaling components of the T cell receptor activation pathway were inhibited by FasL triggering and reverse signalling. In this context, the phosphorylation of ERK1/2, p38 MAPK as well as further upstream acting signaling proteins such as PLCγ was markedly reduced. Notably, the inhibition was also observed in the presence of exogenous rIL-2, indicating that a lack of IL-2 is not the cause of the proliferation block. Taken together, our data argue for a negative reverse signaling capacity of FasL on freshly isolated, TCR-triggered human T cells.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Paulsen, M., Valentin, S. & Janssen, O. Reverse signaling by FasL inhibits primary human T cell activation. Cell Commun Signal 7 (Suppl 1), A23 (2009).

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