T Cell Costimulation Molecules CD80/86 Inhibit Osteoclast Differentiation by Inducing the IDO/Tryptophan Pathway
T Cell Costimulation Molecules CD80/86 Inhibit Osteoclast Differentiation by Inducing the IDO/Tryptophan Pathway
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DOI：
10.1126/scitranslmed.3007764
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发表时间：
2014-05-07
影响因子：
17.1
通讯作者：
Schett, Georg
中科院分区：
文献类型：
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作者：
Bozec, Aline;Zaiss, Mario M.;Schett, Georg
骨吸收是生命过程中骨的生理重塑的重要组成部分。然而，这一过程需要严格控制；过度的骨吸收导致病理性骨质流失、骨质疏松和骨折。我们描述了适应性免疫系统对骨吸收的控制机制。CD80/86是抗原提呈细胞表达并参与T细胞共刺激的一对分子，对骨吸收破骨细胞的产生起负调节作用。cd80 /86缺陷小鼠由于破骨细胞分化增加而出现骨减少。缺乏cd80 /86的破骨细胞逃脱了CTLA-4或调节性T细胞的生理抑制。机制上，CTLA-4参与CD80/86诱导破骨细胞前体中的吲哚胺2,3-双加氧酶（IDO）活化，从而降解色氨酸并促进细胞凋亡。与此同时，ido缺陷小鼠也表现出骨质减少的表型，具有更高数量的破骨细胞前体和破骨细胞。此外，缺乏ido的单核细胞也没有CTLA-4的抗破骨细胞作用。这种分子机制也存在于人类中，因为abatacept（一种CTLA-4免疫球蛋白融合蛋白）靶向CD80/86减少，而ipilimumab抗体阻断CTLA-4增强了外周破骨细胞前体和破骨细胞发生的频率。综上所述，这些数据表明适应性免疫系统，特别是T细胞CD80/86共刺激分子，在骨吸收和骨量保存的生理调节中发挥重要作用，并影响当前和未来药物促进或阻断CTLA-4在人体中的作用的功能。
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.