Modulation of Fas-mediated apoptosis by lipid rafts in T lymphocytes

Patrick Legembre1, Sophie Daburon, Patrick Moreau

  • 1Laboratoire Composantes Innées de la Réponse Immunitaire et Différenciation, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5164, University of Bordeaux, France. patrick.legembre@u-bordeaux2.fr

Insights

Different cell membrane microdomains regulate Fas-mediated apoptosis in human T cells. CD28 recruitment amplifies Fas signaling, while CD55 or CD59 inhibit it, controlling cell death at the membrane level.

Area of Science:

  • Cell Biology
  • Immunology
  • Molecular Biology

Background:

  • Fas-mediated apoptosis differs between cell types, requiring lipid rafts in type I cells but not type II.
  • Understanding the role of specific membrane proteins within these rafts is crucial for deciphering apoptosis regulation.

Purpose of the Study:

  • To investigate the distinct roles of CD28, CD59, and CD55 localization within lipid rafts in modulating Fas signaling in human T cells.
  • To determine if different microdomains differentially affect Fas-induced apoptosis.

Main Methods:

  • Immunofluorescence microscopy to visualize protein localization within lipid rafts.
  • Co-immunoprecipitation assays to study protein interactions.
  • Flow cytometry to assess Fas-mediated apoptosis upon protein coligation or cross-linking.

Main Results:

  • CD28, CD59, and CD55 localize to lipid rafts in human T cells.
  • CD28 concentrates in GM1-enriched microdomains, distinct from CD59 and CD55.
  • CD28 cross-linking forms raft clusters excluding CD59/CD55, and vice versa.
  • Coligation of Fas with CD55/CD59 inhibits apoptosis, while CD28 recruitment amplifies Fas signaling.

Conclusions:

  • Distinct microdomains with unique functional properties exist on the cell surface.
  • The recruitment of specific microdomains differentially modulates the Fas pathway.
  • Fas-induced apoptosis can be precisely controlled at the cytoplasmic membrane level through protein interactions within microdomains.

Related Concept Videos

The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
Phagocytosis of Apoptotic Cells01:17

Phagocytosis of Apoptotic Cells

Cells undergoing apoptosis form apoptotic bodies that must be removed immediately to prevent inflammation, autoimmune diseases, and necrosis. Phagocytosis is carried out by professional phagocytes such as macrophages or  immature dendritic cells. Non-professional phagocytes such as  epithelial cells and fibroblasts also take part in this process; however, they are not as effective as professional phagocytes. 
Normal cells contain receptors that prevent them from being recognized by phagocytes.
Rab Cascades01:25

Rab Cascades

Rab GTPases act in a regulated cascade during membrane fusion, helping the lipid bilayers mix. The Rab family of proteins are active when bound to GTP, and inactive when bound to GDP. Hence, they act as guanine nucleotide-dependent molecular switches. Rab-GTP recognizes and binds to long or short-range tethering proteins to capture the target vesicle. These tethers coordinate with SNAREs on the vesicle and the target membrane to assemble the trans SNARE complex that locks the mixing bilayers.
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
Intracellular Signaling Affects Focal Adhesions01:17

Intracellular Signaling Affects Focal Adhesions

Integrins act both as extracellular input receivers and as intracellular processing activators. As their name suggests, integrins are entirely integrated into the membrane structure. Their hydrophobic membrane-spanning regions interact with the phospholipid bilayer's hydrophobic region. These membrane receptors provide extracellular attachment sites for effectors like hormones and growth factors. They activate intracellular response cascades when their effectors are bound and active.
Some...