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Involvement of the Fas (CD95) system in peripheral cell death and lymphoid organ development
Y Laouar1, A Sarukhan, V Pasqualetto
1INSERM U.345, Institut Necker, Paris, France.
Abstract:
Fas-mediated apoptosis is a form of cell death that operates through a Fas-Fas ligand (FasL) interaction. In this study we investigated the role of the Fas system during development of normal and Fas-mutated lymphocytes. Irradiated RAG2-/-recipients were reconstituted with bone marrow cells from B6 and lpr mice (Fas defective) or from B6 and gld mice (FasL defective), and analyzed for long-term development. The results showed a primary role of the Fas system in peripheral cell death and thymic colonization. In the periphery, the interaction in vivo between Fas+ and Fas-T cell populations indicated that cellular homeostasis was defective. Indeed, we observed a FasL-mediated cytotoxic effect on normal-derived T cells, explaining the dominance of lpr T cells in the mixed chimeras. The Fas mutation affected neither cell activation nor cell proliferation, as the effector (Fas-) and target (Fas+) cells behaved similarly with regard to activation marker expression and cell cycle status. However, Fas-T cells failed to seed the periphery and the thymus in the long term. We suggest that this could be due to the fact that FasL is involved in the structural organization of the lymphoid compartment.
Insights
The Fas system is crucial for lymphocyte homeostasis, regulating peripheral cell death and thymic colonization. FasL-mediated cytotoxicity impacts T cell populations, affecting lymphoid compartment organization.
Area of Science:
- Immunology
- Cell Biology
- Developmental Biology
Background:
- Fas-mediated apoptosis is a key pathway for cell death, involving Fas and Fas ligand (FasL) interactions.
- The role of the Fas system in lymphocyte development and homeostasis requires further elucidation.
Purpose of the Study:
- To investigate the function of the Fas system in the development of normal and Fas-mutated lymphocytes.
- To determine the impact of Fas and FasL defects on T cell homeostasis and lymphoid organ colonization.
Main Methods:
- Utilized a bone marrow chimera model by reconstituting irradiated RAG2-/- recipients with cells from Fas-defective (lpr) and FasL-defective (gld) mice.
- Analyzed long-term lymphocyte development, peripheral cell death, thymic colonization, cell activation, proliferation, and lymphoid compartment structure.
Main Results:
- The Fas system plays a primary role in peripheral T cell death and thymic colonization.
- FasL-mediated cytotoxicity was observed against normal T cells, leading to the dominance of Fas-defective (lpr) T cells in mixed chimeras.
- Fas mutations did not affect T cell activation or proliferation but impaired long-term seeding of the periphery and thymus.
Conclusions:
- The Fas system is essential for maintaining lymphocyte homeostasis and proper lymphoid compartment organization.
- FasL appears to be involved in the structural organization of lymphoid compartments, impacting T cell homing and survival.