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Stimulating Lymphotoxin Receptor on the Dendritic Cells Is Critical for Their Homeostasis and Expansion¹

Department of Pathology, University of Chicago, Chicago IL 60637

The increased number of dendritic cells (DCs) inside lymphoid tissue may contribute to the enhanced priming of lymphocytes. The homeostasis of splenic DCs has mostly been attributed to their migration to the spleen via the chemokine microenvironment induced by lymphotoxin receptor (LTR) signaling on splenic stromal cells. In this study we show that the lack of direct LTR signaling on DCs is associated with the reduction of the number of DCs in the spleen independently of chemokine gradients. LTR^–/– mice have reduced DCs and reduced BrdU incorporation on DCs, and fewer DCs from LTR^–/– mice are detected in the spleen. Furthermore, increased expression of LIGHT (homologous to lymphotoxin, exhibits inducible expression, competes with herpesvirus glycoprotein D for herpes virus entry mediator on T cells) on T cells, a member of the TNF family (TNFSF14) and a ligand for LTR, could dramatically increase the number of T cells and DCs, which leads to severe autoimmune diseases in a LTR-dependent fashion. In vitro, LIGHT could directly promote accumulation of bone marrow-derived DCs. Furthermore, intratumor expression of LIGHT can dramatically expand DCs in situ, and inoculation of DCs into tumor tissues enhanced tumor immunity. Therefore, LTR signaling on DCs is required for their homeostasis during physiology and pathological conditions, and increased LIGHT-LTR interaction could stimulate DC expansion for T cell-mediated immunity.

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