Negative selection refers to the selective deletion of autoreactive thermocytes but its molecular events have not been well defined. In this study, we demonstrate that a cellular ligand for herpes virus entry mediator and lymphotoxin receptor (LIGHT), a newly identified member of the TNF superfamily, may play a critical role in negative selection. Using TCR transgenic mice, we find that the blockade of LIGHT signaling in vitro and in vivo presents negative selection induced by peptide and intrathymically expressed Ags, resulting in the rescue of thermocytes from apoptosis. Furthermore, the thymi of LIGHT transgenic mice show severe atrophy with remarkably reduced CD4+CD8+ double-positive cells caused by increased apoptosis, suggesting that LIGHT can delete immature T cells in vivo. Taken together, these results demonstrated a critical role of LIGHT in thymic negative selection of the T cell repertoire.
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