IMMUNOBIOLOGY Long-lived immature dendritic cells mediated by TRANCE-RANK interaction

Immature dendritic cells (DCs) reside in interstitial tissues (int-DC) or in the epider-mis, where they capture antigen and, thereafter, mature and migrate to draining lymph nodes (LNs), where they present processed antigen to T cells. We have identified int-DCs that express both TRANCE (tumor necrosis factor–related activation-induced cytokine) and RANK (receptor activator of NF-B) and have generated these cells from CD34 human progenitor cells using macrophage colony-stimulating factor (M-CSF). These CD34-derived int-DCs, which are related to macrophages, are long-lived, but addi-tion of soluble RANK leads to significant reduction of cell viability and Bcl-2 expres-sion. This suggests that constitutive TRANCE-RANK interaction is respon-sible for CD34-derived int-DC longevity. Conversely, CD1a DCs express only RANK and are short-lived. However, they can be rescued from cell death either by recombinant soluble TRANCE or by CD34-derived int-DCs. CD34-derived int-DCs mature in response to lipopoly-saccharide (LPS) plus CD40 ligand (L) and become capable of CCL21/CCL19-mediated chemotaxis and naive T-cell ac-tivation. Upon maturation, they lose TRANCE, making them, like CD1a DCs, dependent on exogenous TRANCE for survival. These findings provide evi-dence that TRANCE and RANK play im-portant roles in the homeostasis of DCs