title: T cell costimulation molecules CD80/86 inhibit osteoclast differentiation by inducing the IDO/tryptophan pathway.
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.affiliation: Department of Internal Medicine 3, Rheumatology and Immunology, University of Erlangen-Nuremberg, Erlangen 91054, Germany.
authors.forename: Aline
authors.initials: A
authors.lastname: Bozec
authors.forename: Mario M
authors.initials: MM
authors.lastname: Zaiss
authors.forename: Rosebeth
authors.initials: R
authors.lastname: Kagwiria
authors.forename: Reinhard
authors.initials: R
authors.lastname: Voll
authors.forename: Manfred
authors.initials: M
authors.lastname: Rauh
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.forename: Sandra
authors.initials: S
authors.lastname: Mueller-Schmucker
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kroczek
authors.forename: Lucie
authors.initials: L
authors.lastname: Heinzerling
authors.forename: Muriel
authors.initials: M
authors.lastname: Moser
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mellor
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: David
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology*; D051940:B7-2 Antigen / Q000235:genetics / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology*; D013601:T-Lymphocytes / Q000276:immunology*; D014364:Tryptophan / Q000378:metabolism*
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497964:CD86 protein, human; D060908:CTLA-4 Antigen; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016328:NF-kappa B; D014364:Tryptophan