Potential involvement of TRAIL in Treg cell-mediated osteoclast suppression: Comment on the article by Zaiss et al

In a study recently reported in Arthritis & Rheumatism, Zaiss et al elegantly demonstrated that CD4+,CD25+Treg cells purified from mouse spleens inhibit macrophage colony-stimulating factor- and RANKL-dependent osteoclast formation of bone marrow preosteoclasts, in a dose-dependent manner. Similar findings were independently reported by Kim et al, who used human peripheral blood monocytes as a source of preosteoclasts. The findings of Zaiss and colleagues are particularly interesting given that Treg cells are known to be potent immunosuppressive cells that are active in controlling normal and pathologic immune responses. Although some models provide evidence that bystander suppression is dependent on cell-cell contact, other studies have emphasized the role of soluble cytokines. Thus, the mode of action and immunologic regulatory molecular mechanisms mediated by Treg lymphocytes are still largely unknown. In this respect, it is noteworthy that Ren and colleagues have recently demonstrated a key role of the tumor necrosis factor (TNF) superfamily member TRAIL in mediating Treg cell immunosuppression. Blocking of the TRAIL/TRAILR-2 pathway resulted in a significant reduction of the suppressive activity as well as the cytotoxic effects of Treg cells in vitro and in vivo. A potential linkage between the findings reported by Zaiss et al and Kim et al and those reported by Ren et al comes from previous studies by our group and others, demonstrating that TRAIL plays a significant role in inhibiting the differentiation of both murine and human macrophage-derived preosteoclasts as well as in inducing apoptosis of mature osteoclasts. Since mouse preosteoclasts express only TRAILR-2 while human peripheral blood-derived preosteoclasts express both death receptors TRAILR-1 and TRAILR-2 as well as the decoy receptor TRAILR-4, these findings suggest that TRAILR-2 is the key receptor mediating the antiosteoclastic activity of TRAIL. TRAIL, like other members of the TNF superfamily of cytokines, is expressed as either a transmembrane or a soluble protein, and it therefore, in principle, might contribute to both cell-associated and cytokine-mediated antiosteoclastic activity of Treg cells. Of note, recent evidence also supports the notion that impaired CD4+,CD25+ Treg cell function has a role in the pathogenesis of rheumatoid arthritis, the prototype of immune-mediated chronic inflammatory diseases. Thus, in light of the imminent use of recombinant TRAIL and humanized anti-TRAILR-2 antibody for the treatment of neoplastic and chronic inflammatory disorders, understanding the role of TRAIL in Treg-mediated osteoclast suppression also warrants further investigation from a therapy perspective.