Abstract
Clonotypic elimination of activated T cells through Fas–Fas ligand (CD95–CD95L) interactions is one mechanism of peripheral self-tolerance. T cell receptor (TCR) stimuli trigger FasL synthesis but also sensitize activated T cells to Fas-mediated apoptosis through an unknown mechanism. Here we show that TCR restimulation of activated human CD4+ T cells resulted in Fas translocation into lipid raft microdomains before binding FasL, rendering these cells sensitive to apoptosis after stimulation with bivalent antibody or FasL. Disruption of lipid rafts reduced sensitivity to Fas-mediated apoptosis after TCR restimulation. Thus, the redistribution of Fas and other tumor necrosis factor family receptors into and out of lipid rafts may dynamically regulate the efficiency and outcomes of signaling by these receptors.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Lenardo, M. et al. Mature T lymphocyte apoptosis—immune regulation in a dynamic and unpredictable antigenic environment. Annu. Rev. Immunol. 17, 221–253 (1999).
Abbas, A.K. Die and let live: eliminating dangerous lymphocytes. Cell 84, 655–657 (1996).
Hildeman, D.A. et al. Activated T cell death in vivo mediated by proapoptotic bcl-2 family member bim. Immunity 16, 759–767 (2002).
Hornung, F., Zheng, L. & Lenardo, M.J. Maintenance of clonotype specificity in CD95/Apo-1/Fas-mediated apoptosis of mature T lymphocytes. J. Immunol. 159, 3816–3822 (1997).
Combadiere, B. et al. Differential TCR signaling regulates apoptosis and immunopathology during antigen responses in vivo. Immunity 9, 305–313 (1998).
Van Parijs, L., Peterson, D.A. & Abbas, A.K. The Fas/Fas ligand pathway and Bcl-2 regulate T cell responses to model self and foreign antigens. Immunity 8, 265–274 (1998).
Wong, B., Arron, J. & Choi, Y. T cell receptor signals enhance susceptibility to Fas-mediated apoptosis. J. Exp. Med. 186, 1939–1944 (1997).
Scaffidi, C. et al. Two CD95 (APO-1/Fas) signaling pathways. Embo. J. 17, 1675–1687 (1998).
Dykstra, M., Cherukuri, A., Sohn, H.W., Tzeng, S.J. & Pierce, S.K. Location is everything: Lipid rafts and immune cell signaling. Annu. Rev. Immunol. 21, 457–481 (2003).
Sedwick, C.E. & Altman, A. Ordered just so: lipid rafts and lymphocyte function. Sci. STKE 2002, RE2 (2002).
Scheel-Toellner, D. et al. The death-inducing signalling complex is recruited to lipid rafts in Fas-induced apoptosis. Biochem. Biophys. Res. Commun. 297, 876–879 (2002).
Hueber, A.O., Bernard, A.M., Herincs, Z., Couzinet, A. & He, H.T. An essential role for membrane rafts in the initiation of Fas/CD95-triggered cell death in mouse thymocytes. EMBO Rep. 3, 190–196 (2002).
Garofalo, T. et al. Association of the death-inducing signaling complex with microdomains after triggering through CD95/Fas. Evidence for caspase-8-ganglioside interaction in T cells. J. Biol. Chem. 278, 8309–8315 (2003).
Cremesti, A. et al. Ceramide enables fas to cap and kill. J. Biol. Chem. 276, 23954–23961 (2001).
Legler, D.F., Micheau, O., Doucey, M.A., Tschopp, J. & Bron, C. Recruitment of TNF receptor 1 to lipid rafts is essential for TNFα-mediated NF-κB activation. Immunity 18, 655–664 (2003).
Algeciras-Schimnich, A. et al. Molecular ordering of the initial signaling events of CD95. Mol. Cell. Biol. 22, 207–220 (2002).
Huang, D.C. et al. Activation of Fas by FasL induces apoptosis by a mechanism that cannot be blocked by Bcl-2 or Bcl-x(L). Proc. Natl. Acad. Sci. USA 96, 14871–14876 (1999).
Keller, P. & Simons, K. Cholesterol is required for surface transport of influenza virus hemagglutinin. J. Cell. Biol. 140, 1357–1367 (1998).
Siegel, R.M. et al. Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations. Science 288, 2354–2357 (2000).
Chan, F.K. et al. A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science 288, 2351–2354 (2000).
Zacharias, D.A., Violin, J.D., Newton, A.C. & Tsien, R.Y. Partitioning of lipid-modified monomeric GFPs into membrane microdomains of live cells. Science 296, 913–916 (2002).
Friedrichson, T. & Kurzchalia, T.V. Microdomains of GPI-anchored proteins in living cells revealed by crosslinking. Nature 394, 802–805 (1998).
Scaffidi, C., Schmitz, I., Krammer, P.H. & Peter, M.E. The role of c-FLIP in modulation of CD95-induced apoptosis. J. Biol. Chem. 274, 1541–1548 (1999).
Van Parijs, L., Ibraghimov, A. & Abbas, A.K. The roles of costimulation and Fas in T cell apoptosis and peripheral tolerance. Immunity 4, 321–328 (1996).
Siegel, R.M., Chan, F.K., Chun, H.J. & Lenardo, M.J. The multifaceted role of Fas signaling in immune cell homeostasis and autoimmunity. Nat. Immunol. 1, 469–474 (2000).
Micheau, O. et al. The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signaling complex. J. Biol. Chem. 277, 45162–45171 (2002).
Strasser, A., Harris, A.W., Huang, D.C., Krammer, P.H. & Cory, S. Bcl-2 and Fas/APO-1 regulate distinct pathways to lymphocyte apoptosis. Embo. J. 14, 6136–6147 (1995).
Sprent, J. & Kishimoto, H. The thymus and negative selection. Immunol. Rev. 185, 126–135 (2002).
Micheau, O. & Tschopp, J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114, 181–190 (2003).
Parlato, S. et al. CD95 (APO-1/Fas) linkage to the actin cytoskeleton through ezrin in human T lymphocytes: a novel regulatory mechanism of the CD95 apoptotic pathway. Embo. J. 19, 5123–5134 (2000).
Martin, D.A. et al. Defective CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative syndrome, type Ia. Proc. Natl. Acad. Sci. USA 96, 4552–4557 (1999).
Sproul, T.W., Malapati, S., Kim, J. & Pierce, S.K. Cutting edge: B cell antigen receptor signaling occurs outside lipid rafts in immature B cells. J. Immunol. 165, 6020–6023 (2000).
Gaide, O. et al. CARMA1 is a critical lipid raft-associated regulator of TCR-induced NF-κB activation. Nat. Immunol. 3, 836–843 (2002).
Legler, D.F., Doucey, M.A., Cerottini, J.C., Bron, C. & Luescher, I.F. Selective inhibition of CTL activation by a dipalmitoyl-phospholipid that prevents the recruitment of signaling molecules to lipid rafts. FASEB J. 15, 1601–1603 (2001).
Acknowledgements
We thank M. Lenardo, S. Pierce, J. Rivera and P. Schwartzberg for critically reviewing the manuscript; L. Zheng, F. Hornung and I. Stefanova for discussions; and A. Cherukuri for technical assistance. J.R.M. is a Howard Hughes Medical Institute–National Institutes of Health Research Scholar and is supported by grant 5-T32-ES007079 from the US National Institute of Environmental Health Sciences (National Institutes of Health).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Rights and permissions
About this article
Cite this article
Muppidi, J., Siegel, R. Ligand-independent redistribution of Fas (CD95) into lipid rafts mediates clonotypic T cell death. Nat Immunol 5, 182–189 (2004). https://doi.org/10.1038/ni1024
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ni1024
This article is cited by
-
Characterizing the regulatory Fas (CD95) epitope critical for agonist antibody targeting and CAR-T bystander function in ovarian cancer
Cell Death & Differentiation (2023)
-
FOXP3 protects conventional human T cells from premature restimulation-induced cell death
Cellular & Molecular Immunology (2021)
-
Squalene synthase promotes the invasion of lung cancer cells via the osteopontin/ERK pathway
Oncogenesis (2020)
-
Modulation of CD95-mediated signaling by post-translational modifications: towards understanding CD95 signaling networks
Apoptosis (2019)
-
Depletion of membrane cholesterol compromised caspase-8 imparts in autophagy induction and inhibition of cell migration in cancer cells
Cancer Cell International (2018)