Emerging Functions of RANKL in Lymphoid Tissues

Abstract

The tumor necrosis factor superfamily (TNFSF) members play pivotal roles in embryonic development of lymphoid tissue and their homeostasis. RANKL (Receptor activator of NF-κB ligand, also called TRANCE, TNFSF11) is recognized as an important player in bone homeostasis and lymphoid tissue formation. In its absence bone mass control is deregulated and lymph nodes fail to develop. While its function in bone is well described, there is still little functional insight into the action of RANKL in lymphoid tissue development and homeostasis. Here we provide an overview of the known functions of RANKL, its signaling receptor RANK and its decoy receptor OPG from the perspective of lymphoid tissue development and immune activation in the mouse. Expressed by the hematopoietic lymphoid tissue inducing (LTi) cells and the mesenchymal lymphoid tissue organizer (LTo) cells, RANKL was shown to stimulate Lymphotoxin (LT) expression and to be implicated in LTi cell accumulation. Our recent finding that RANKL also triggers proliferation of adult lymph node stroma suggests that RANKL may furthermore directly activate LTo cells. Beyond bone, the RANKL-RANK-OPG triad plays important roles in immunobiology that are waiting to be unraveled.

Keywords: LTi; LTo; OPG; TNFSF11; TRANCE; lymph node; lymphoid organs; stroma.

Figure 1

RANKL function in the bone, the adaptive immune system and the vascular system. (A) RANKL produced by bone marrow stroma (osteoblasts and osteocytes) directs the differentiation of preosteoclasts of the myeloid lineage into mature osteoclasts. Stroma-derived OPG negatively regulates RANKL-RANK interaction. (B) Activated T cells express RANKL that stimulates dendritic cell survival and maturation. (C) Endothelium is a source for RANKL and OPG. RANK-activation of endothelial cells supports cell survival and promotes angiogenesis.

Figure 2

RANKL-dependent amplification loops in SLO development. SLO development during embryogenesis is initiated by the recruitment of lymphoid tissue inducer (LTi) cells to a rudimentary organ anlage composed of mesenchymal lymphoid tissue organizer (LTo) cell progenitors. This step is followed by a cross-talk between LTi cells that express RANKL, RANK, and LTαβ and LTo cells that carry LTβR . Engagement of the latter induces the maturation of LTo cells to express RANKL and chemokines that attract larger numbers of LTi cells that upon clustering with LTo cells initiate LN organization. LTo cells also express RANKL. The current model of LN development indicates that a positive feedback loop takes place between LTo and LTi cells via RANKL-RANK and LTαβ-LTβR amplifying the early stages of LN development . If LTo cells expressed also RANK, a second (autocrine) loop may occur, leading to a direct activation of LTo cells .