T cell costimulation molecules CD80/86 inhibit osteoclast differentiation by inducing the IDO/tryptophan pathway

Aline Bozec, Mario M. Zaiss, Rosebeth Kagwiria, Reinhard Voll, Manfred Rauh, Zhu Chen, Sandra Mueller-Schmucker, Richard A. Kroczek, Lucie Heinzerling, Muriel Moser, Andrew L. Mellor, Jean Pierre David, Georg Schett

Research output: Contribution to journalArticle

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Abstract

Bone resorption is seminal for the physiological remodeling of bone during life. However, this process needs to be strictly controlled; excessive bone resorption results in pathologic bone loss, osteoporosis, and fracture. We describe a control mechanism of bone resorption by the adaptive immune system. CD80/86, a pair of molecules expressed by antigen-presenting cells and involved in T cell costimulation, act as negative regulator for the generation of bone-resorbing osteoclasts. CD80/86-deficient mice were osteopenic because of increased osteoclast differentiation. CD80/86-deficient osteoclasts escaped physiological inhibition by CTLA-4 or regulatory T cells. Mechanistically, engagement of CD80/86 by CTLA-4 induced activation of the enzyme indoleamine 2,3-dioxygenase (IDO) in osteoclast precursors, which degraded tryptophan and promoted apoptosis. Concordantly, IDO-deficient mice also showed an osteopenic bone phenotype with higher numbers of osteoclast precursors and osteoclasts. Also, IDO-deficient mononuclear cells escaped the anti-osteoclastogenic effect of CTLA-4. This molecular mechanism was also present in humans because targeting CD80/86 by abatacept, a CTLA-4-immunoglobulin fusion protein, reduced, whereas blockade of CTLA-4 by ipilimumab antibody enhanced, the frequency of peripheral osteoclast precursors and osteoclastogenesis. In summary, these data show an important role of the adaptive immune system, in particular T cell CD80/86 costimulation molecules, in the physiological regulation of bone resorption and preservation of bone mass, as well as affect the understanding of the function of current and future drugs fostering or blocking the effects of CTLA-4 in humans.

Original languageEnglish (US)
Article number235ra60
JournalScience Translational Medicine
Volume6
Issue number235
DOIs
StatePublished - May 7 2014

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Osteoclasts
Tryptophan
T-Lymphocytes
Bone Resorption
Bone and Bones
Immune System
Enzyme Activation
Foster Home Care
Bone Remodeling
Antigen-Presenting Cells
Regulatory T-Lymphocytes
Osteogenesis
Osteoporosis
Immunoglobulins
Apoptosis
Phenotype
Antibodies

ASJC Scopus subject areas

  • Medicine(all)

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T cell costimulation molecules CD80/86 inhibit osteoclast differentiation by inducing the IDO/tryptophan pathway. / Bozec, Aline; Zaiss, Mario M.; Kagwiria, Rosebeth; Voll, Reinhard; Rauh, Manfred; Chen, Zhu; Mueller-Schmucker, Sandra; Kroczek, Richard A.; Heinzerling, Lucie; Moser, Muriel; Mellor, Andrew L.; David, Jean Pierre; Schett, Georg.

In: Science Translational Medicine, Vol. 6, No. 235, 235ra60, 07.05.2014.

Research output: Contribution to journalArticle

Bozec, A, Zaiss, MM, Kagwiria, R, Voll, R, Rauh, M, Chen, Z, Mueller-Schmucker, S, Kroczek, RA, Heinzerling, L, Moser, M, Mellor, AL, David, JP & Schett, G 2014, 'T cell costimulation molecules CD80/86 inhibit osteoclast differentiation by inducing the IDO/tryptophan pathway', Science Translational Medicine, vol. 6, no. 235, 235ra60. https://doi.org/10.1126/scitranslmed.3007764
Bozec, Aline ; Zaiss, Mario M. ; Kagwiria, Rosebeth ; Voll, Reinhard ; Rauh, Manfred ; Chen, Zhu ; Mueller-Schmucker, Sandra ; Kroczek, Richard A. ; Heinzerling, Lucie ; Moser, Muriel ; Mellor, Andrew L. ; David, Jean Pierre ; Schett, Georg. / T cell costimulation molecules CD80/86 inhibit osteoclast differentiation by inducing the IDO/tryptophan pathway. In: Science Translational Medicine. 2014 ; Vol. 6, No. 235.
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AU - Zaiss, Mario M.

AU - Kagwiria, Rosebeth

AU - Voll, Reinhard

AU - Rauh, Manfred

AU - Chen, Zhu

AU - Mueller-Schmucker, Sandra

AU - Kroczek, Richard A.

AU - Heinzerling, Lucie

AU - Moser, Muriel

AU - Mellor, Andrew L.

AU - David, Jean Pierre

AU - Schett, Georg

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AB - Bone resorption is seminal for the physiological remodeling of bone during life. However, this process needs to be strictly controlled; excessive bone resorption results in pathologic bone loss, osteoporosis, and fracture. We describe a control mechanism of bone resorption by the adaptive immune system. CD80/86, a pair of molecules expressed by antigen-presenting cells and involved in T cell costimulation, act as negative regulator for the generation of bone-resorbing osteoclasts. CD80/86-deficient mice were osteopenic because of increased osteoclast differentiation. CD80/86-deficient osteoclasts escaped physiological inhibition by CTLA-4 or regulatory T cells. Mechanistically, engagement of CD80/86 by CTLA-4 induced activation of the enzyme indoleamine 2,3-dioxygenase (IDO) in osteoclast precursors, which degraded tryptophan and promoted apoptosis. Concordantly, IDO-deficient mice also showed an osteopenic bone phenotype with higher numbers of osteoclast precursors and osteoclasts. Also, IDO-deficient mononuclear cells escaped the anti-osteoclastogenic effect of CTLA-4. This molecular mechanism was also present in humans because targeting CD80/86 by abatacept, a CTLA-4-immunoglobulin fusion protein, reduced, whereas blockade of CTLA-4 by ipilimumab antibody enhanced, the frequency of peripheral osteoclast precursors and osteoclastogenesis. In summary, these data show an important role of the adaptive immune system, in particular T cell CD80/86 costimulation molecules, in the physiological regulation of bone resorption and preservation of bone mass, as well as affect the understanding of the function of current and future drugs fostering or blocking the effects of CTLA-4 in humans.

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