T Cell Costimulation Molecules CD80/86 Inhibit Osteoclast Differentiation by Inducing the IDO/Tryptophan Pathway

Bozec A, Zaiss M, Kagwiria R, Voll R, Rauh M, Chen Z, Müller-Schmucker S, Kroczek RA, Heinzerling L, Moser M, Mellor AL, David JP, Schett G (2014)

Publication Type: Journal article

Publication year: 2014

Journal

Science Translational Medicine American Association for the Advancement of Science

Publisher: American Association for the Advancement of Science

Book Volume: 6

Pages Range: 235ra60

Journal Issue: 235

DOI: 10.1126/scitranslmed.3007764

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.

Authors with CRIS profile

Aline Bozec Juniorprofessur für Osteoimmunologie Mario Zaiss Department of Medicine 3 – Rheumatology and Immunology Rosebeth Kagwiria Professur für Genetik Manfred Rauh Department of Paediatrics and Adolescent Medicine Zhu Chen Lehrstuhl für Innere Medizin III Sandra Müller-Schmucker Institute of Clinical and Molecular Virology Lucie Heinzerling Department of Dermatology Georg Schett Lehrstuhl für Innere Medizin III

Involved external institutions

Albert-Ludwigs-Universität Freiburg DE Germany (DE) Robert Koch-Institut (RKI) DE Germany (DE) Université libre de Bruxelles (ULB) / Free University of Brussels BE Belgium (BE) Augusta University US United States (USA) (US) Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE)

How to cite

APA:

Bozec, A., Zaiss, M., Kagwiria, R., Voll, R., Rauh, M., Chen, Z.,... Schett, G. (2014). T Cell Costimulation Molecules CD80/86 Inhibit Osteoclast Differentiation by Inducing the IDO/Tryptophan Pathway. Science Translational Medicine, 6(235), 235ra60. https://doi.org/10.1126/scitranslmed.3007764

MLA:

Bozec, Aline, et al. "T Cell Costimulation Molecules CD80/86 Inhibit Osteoclast Differentiation by Inducing the IDO/Tryptophan Pathway." Science Translational Medicine 6.235 (2014): 235ra60.

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