Patients with X-linked hyper-IgM syndrome (XHIM), an inherited immune deficiency disorder caused by mutations in the gene encoding CD40 ligand (CD40L), have prominent osteopenia, leading to low-energy fractures, of unknown mechanism. This clinical observation prompted the investigators to ask whether CD40L deficiency may contribute to an imbalance in bone mineral homeostasis [1]. In this study, they show that, compared with age- and sex-matched normal controls, XHIM patients have significantly lower bone mineral density (BMD) and have elevated levels of N-terminal telopeptides of type I collagen (NTX), a urinary marker indicative of osteoclast activity.

Recognizing that activated T cells express surface receptor activator of NF-kB ligand (RANKL) and can induce osteoclast differentiation of myeloid cells expressing RANK, they assessed the capacity of wild-type T cells and CD40L-/- T cells to induce osteoclastogenesis in vitro. Relative to wild-type T cells, activated CD40L-/- T cells from both humans and mice promoted robust osteoclast differentiation of myeloid cells. Whereas activated CD40L-/- T cells had normal expression of RANKL, they were deficient in IFN-γ production. In subsequent studies, they cultured activated CD40L-/- T cells in the presence of IFN-γ, and found that the osteoclastic capacity of CD40L-/- T cells could be greatly diminished. IFN-γ signaling leads to the proteosomal degradation of tumor necrosis factor receptor-associated factor 6 (TRAF6), which is recruited following RANK stimulation and activates intracellular pathways downstream. IFN-γ can therefore have an inhibitory effect on RANK intracellular signaling and osteoclast activity.

These results show that CD40L can influence RANKL signaling through T cell priming, and thus they demonstrate a regulatory role for CD40L in bone mineralization that is absent in patients with X-linked hyper-IgM syndrome.

1. Lopez-Granados E et al. Proc Natl Acad Sci USA. 2007;104: 5056-5061.