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Degranulation plays an essential part in regulating cell surface expression of Fas ligand in T cells and natural killer cells

Nature Medicine volume 5, pages 90–96 (1999)Cite this article

Abstract

Fas ligand (FasL) triggers apoptosis during cytotoxicity mediated by cytotoxic T lymphocytes and during immune downregulation 1 . The ability of T cells and natural killer cells to trigger apoptosis through this mechanism is controlled by the cell surface expression of FasL ( ref. 2 ). Because FasL expression is upregulated on activation 2, 3 , FasL was thought to be delivered directly to the cell surface. Here we show that newly synthesized FasL is stored in specialized secretory lysosomes in both CD4 + and CD8 + T cells and natural killer cells, and that polarized degranulation controls the delivery of FasL to the cell surface. In this way, FasL-mediated apoptosis is finely controlled by receptor-mediated target-cell recognition. The cytoplasmic tail of FasL contains signals that sort FasL to secretory lysosomes in hemopoietic cells. This pathway may provide a general mechanism for controlling the cell surface appearance of proteins involved in immune regulation.

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Figure 1: a, Intracellular localization of FasL in the human NK cell line YT.
Figure 2: FasL is localized in intracellular granules in a CD8+ CTL clone, GC8+e, and is polarized towards the specific target cell on antigen recognition.
Figure 3: Degranulation controls the appearance of FasL on the cell surface.
Figure 4: FasL contains signals for targeting to the secretory lysosomes.
Figure 5: Subcellular distribution of FasL/CD69 chimera molecules in RBL cells.

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Acknowledgements

The authors thank J. Kaufman, G. MacPherson, J. Stinchcombe and H. Waldmann for critical reading of the manuscript and discussions. The work was supported by grants from the Wellcome Trust (040825 and 050613).

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  1. Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE

    G. Bossi & G.M. Griffiths

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Correspondence to G.M. Griffiths.

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Bossi, G., Griffiths, G. Degranulation plays an essential part in regulating cell surface expression of Fas ligand in T cells and natural killer cells. Nat Med 5, 90–96 (1999). https://doi.org/10.1038/4779

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