INVOLVEMENT OF THE FAS (CD95) SYSTEM IN PERIPHERAL CELL-DEATH AND LYMPHOID ORGAN DEVELOPMENT

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 ly mphocytes. Irradiated RAG2(-/-) recipients were reconstituted with bon e marrow cells from B6 and Ipr mice (Fas defective) or from B6 and gld mice (FasL defective), and analyzed for long-term development. The re sults showed a primary role of the Fas system in peripheral cell death and thymic colonization. In the periphery, the interaction in vivo be tween Fas(+) and Fas(-) T cell populations indicated that cellular hom eostasis was defective. Indeed, we observed a FasL-mediated cytotoxic effect on normal-derived T cells, explaining the dominance of Ipr T ce lls in the mixed chimeras. The Fas mutation affected neither cell acti vation nor cell proliferation, as the effector (Fas(-)) and target (Fa s(+)) cells behaved similarly with regard to activation marker express ion 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 Fast is involved in the structural organizatio n of the lymphoid compartment.