Treg cells suppress osteoclast formation: a new link between the immune system and bone.
OBJECTIVE
To investigate whether Treg cells can suppress osteoclast differentiation, and to define a new potential link between the immune system and the skeleton.


METHODS
Regulatory CD4+,CD25+,Foxp3+ T cells were isolated and purified from the spleen and cocultured with CD11b+ osteoclast precursor cells isolated from bone marrow. Osteoclastogenesis and bone erosion were assessed by tartrate-resistant acid phosphatase staining and pit resorption assay, respectively. In addition, Transwell experiments and cytokine-blocking experiments were performed to define the mechanisms of interaction between Treg cells and osteoclasts.


RESULTS
CD4+,CD25+,Foxp3+ T cells, but not CD4+,CD25- T cells, dose dependently inhibited macrophage colony-stimulating factor- and RANKL-dependent osteoclast formation. Pit formation was inhibited by up to 80% when Treg cells were added. The blockade of osteoclast formation was not based on the alteration of RANKL/osteoprotegerin balance but was essentially dependent on direct cell-cell contact via CTLA-4. Treg cell-mediated expression of transforming growth factor beta, interleukin-4 (IL-4), and IL-10 contributed but was not essential to the inhibitory effect on osteoclastogenesis.


CONCLUSIONS
These data show that CD4+,CD25+,Foxp3+ Treg cells suppress osteoclast formation, provide a new link between the immune system and bone, and extend our knowledge on regulation of bone homeostasis by the immune system.
Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Krankenhausstrasse 12, Erlangen, Germany.
Mario M
MM
Zaiss
Roland
R
Axmann
Jochen
J
Zwerina
Karin
K
Polzer
Eva
E
Gückel
Alla
A
Skapenko
Hendrik
H
Schulze-Koops
Nikki
N
Horwood
Andrew
A
Cope
Georg
G
Schett
D000818:Animals; D015703:Antigens, CD / Q000494:pharmacology; D000943:Antigens, Differentiation / Q000494:pharmacology; D001842:Bone and Bones / Q000166:cytology / Q000502:physiology*; D018845:CD11 Antigens / Q000378:metabolism; D060908:CTLA-4 Antigen; D002450:Cell Communication / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007107:Immune System / Q000502:physiology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000166:cytology / Q000276:immunology*; D053245:RANK Ligand / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000502:physiology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018845:CD11 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D016173:Macrophage Colony-Stimulating Factor