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Extracellular matrix interacts with soluble CD95L: Retention and enhancement of cytotoxicity

Nature Immunology volume 2, pages 333–337 (2001)Cite this article

Abstract

Fas ligand (CD95L) is synthesized both on the cell surface membrane and in a soluble form. Although CD95L contributes to immune privilege in the cornea and testis, the functions of these alternatively processed proteins are not well understood. Some reports suggest that the cytotoxicity of soluble CD95L is insignificant, whereas others show potent responses in vivo, including hepatocyte apoptosis that causes liver failure. We show here that extracellular matrix proteins interact with soluble CD95L and potentiate its pro-apoptotic activity. The cytotoxicity of supernatants from CD95L-expressing cells was increased by incubation on tissue culture plates coated with these matrix proteins; this effect was mediated by trimeric soluble CD95L. With the use of immunoprecipitation, it was found that CD95L binds directly to fibronectin. In addition, immunohistochemical analysis of the cornea revealed that soluble CD95L binds primarily to extracellular matrix. The retention of soluble CD95L on extracellular matrices is likely to play an important role in the development of peripheral tolerance in immune-privileged sites.

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Figure 1: The pro-apoptotic activity of soluble CD95L is enhanced by incubation with extracellular matrix proteins.
Figure 2: Size-exclusion column chromatography of soluble CD95L.
Figure 3: A distinct mutation affects soluble CD95L cytotoxicity on extracellular matrix.
Figure 4: Immunohistochemical localization of CD95L to the extracellular matrix in the anterior chamber of the eye.

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Acknowledgements

We thank D. Gschwend, C. Davis, N. Barrett and J. Stein for manuscript preparation; L. L. Xu for the preparation of the slides for histological analysis; and members of the Nabel laboratory for their helpful advice and comments.

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  1. Kazunori Aoki

    Present address: National Cancer Center Research Institute, Section for Studies on Host-Immune Response, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo, 104-0045, Japan

Authors and Affiliations

  1. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 40 Convent Drive, Bethesda, 20892-3005, MD, USA

    Kazunori Aoki, Masayuki Kurooka, Jian-Jun Chen, Jerzy Petryniak & Gary J. Nabel

  2. National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, 20892, MD, USA

    Elizabeth G. Nabel

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Correspondence to Gary J. Nabel.

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Aoki, K., Kurooka, M., Chen, JJ. et al. Extracellular matrix interacts with soluble CD95L: Retention and enhancement of cytotoxicity. Nat Immunol 2, 333–337 (2001). https://doi.org/10.1038/86336

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