Abstract
BackgroundOsteoclasts are the body’s sole bone resorbing cells. Cytokines produced by pro-inflammatory effector T-cells (TEFF) increase bone resorption by osteoclasts. Prolonged exposure to the TEFF produced cytokines leads to bone erosion diseases such as osteoporosis and rheumatoid arthritis. The crosstalk between T-cells and osteoclasts has been termed osteoimmunology. We have previously shown that under non-inflammatory conditions, murine osteoclasts can recruit naïve CD8 T-cells and activate these T-cells to induce CD25 and FoxP3 (TcREG). The activation of CD8 T-cells by osteoclasts also induced the cytokines IL-2, IL-6, IL-10 and IFN-γ. Individually, these cytokines can activate or suppress osteoclast resorption.Principal FindingsTo determine the net effect of TcREG on osteoclast activity we used a number of in vitro assays. We found that TcREG can potently and directly suppress bone resorption by osteoclasts. TcREG could suppress osteoclast differentiation and resorption by mature osteoclasts, but did not affect their survival. Additionally, we showed that TcREG suppress cytoskeletal reorganization in mature osteoclasts. Whereas induction of TcREG by osteoclasts is antigen-dependent, suppression of osteoclasts by TcREG does not require antigen or re-stimulation. We demonstrated that antibody blockade of IL-6, IL-10 or IFN-γ relieved suppression. The suppression did not require direct contact between the TcREG and osteoclasts.SignificanceWe have determined that osteoclast-induced TcREG can suppress osteoclast activity, forming a negative feedback system. As the CD8 T-cells are activated in the absence of inflammatory signals, these observations suggest that this regulatory loop may play a role in regulating skeletal homeostasis. Our results provide the first documentation of suppression of osteoclast activity by CD8 regulatory T-cells and thus, extend the purview of osteoimmunology.
Highlights
The skeletal system is dynamically and constantly remodeled throughout life to maintain bone integrity
The induction of FoxP3 in the presence of antigen was assayed by both multicolor flow cytometry and by reverse transcription (RT) of RNA isolated from the co-culture, followed by PCR
We show that only mature osteoclasts have the ability to induce FoxP3 as the osteoclast precursors could not induce the regulatory phenotype in CD8 T-cells
Summary
The skeletal system is dynamically and constantly remodeled throughout life to maintain bone integrity. Two cells play a key role in remodeling bone: osteoclasts and osteoblasts. Osteoclasts are large multinucleated cells that are the principal, if not sole, bone resorbing cells in the body. Osteoblasts provide essential signals for, and regulate the differentiation of, the myeloid lineage osteoclast precursors by producing macrophage colony-stimulating factor (M-CSF), receptor activator of NF-kB ligand (RANKL; Tnfsf11) and other co-stimulatory factors in the bone marrow [2,3,4,5]. Osteoclasts are the body’s sole bone resorbing cells. Cytokines produced by pro-inflammatory effector T-cells (TEFF) increase bone resorption by osteoclasts. We have previously shown that under non-inflammatory conditions, murine osteoclasts can recruit naıve CD8 T-cells and activate these T-cells to induce CD25 and FoxP3 (TcREG). The activation of CD8 T-cells by osteoclasts induced the cytokines IL-2, IL-6, IL-10 and IFN-c.
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