Human Osteoclasts Are Inducible Immunosuppressive Cells in Response to T cell–Derived IFN-γ and CD40 Ligand In Vitro

Abstract

Osteoclasts (OCs) are bone resorbing cells whose activity can be regulated by activated T cells and their cytokines. However, the immune function of OCs is largely unknown. In this study, we found that as bystanders, human OCs effectively suppressed T-cell proliferation induced by allogeneic, microbial antigenic and T-cell receptor stimuli in vitro. Mechanistic studies revealed that T cell-derived IFN-γ and CD40 ligand (CD40L) induced the expression of indoleamine 2,3-dioxygenase (IDO) in OCs, which mediated the immunosuppressive function on T-cell proliferation through depleting tryptophan. Neutralizing IFN-γ and blocking CD40L, and silencing or inhibiting IDO in OCs restored T-cell proliferation in the presence of OCs. Our data reveal a novel function of human OCs as inducible immunosuppressive cells, and a feedback loop between OCs and activated T cells. Thus, this study provides new insight into the mechanism of the immunosuppressive function of OCs, and may be helpful for developing novel therapeutic strategies for human diseases involving both the bone and immune systems.

Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication

“…T cells require adequate Trp levels for survival and effector function; therefore, IDO-mediated Trp deficiency results in T-cell tolerance and impaired effector function, as well as promotes the differentiation of naive CD4 T cells into regulatory T cells. 40 Consistent with a precious study, 41 we also show that IDO in OCs mediates the immunosuppression of T cells. IDO was significantly increased in BM plasma of MM patients.…”

Osteoimmunology and Beyond

“…Menopausal estrogen decline leads to proliferation and activation of T cells by increasing MHCII expression on monocytes and APC function and by inhibiting T cell apoptosis. These effects leads to the expansion of activated T lymphocytes resulting in hyperproduction of inflammatory cytokines and chronic OC stimulation which is responsible for bone loss and increased fracture risk [76,77]. …”

Osteoimmunology: from mice to humans

“…1 More recently it has been suggested that IFNg is responsible for the ability of OCs to act as antigen presenting cells (APCs) and to modulate T-cell proliferation. 4 TNFa and RANKL are well known pro-osteoclastogenic cytokines. 5 TNF-a induces OC formation in the presence of adequate levels of RANKL, 5 upregulates stromal cell production of RANKL and increases the responsiveness of OC precursors to RANKL.…”