Department of Medicine, and Immunotherapy Center, Georgia Health Sciences University, Augusta, GA 30912, USA.
Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):3909-14. doi: 10.1073/pnas.1117736109. Epub 2012 Feb 21.
Tolerance to self-antigens present in apoptotic cells is critical to maintain immune-homeostasis and prevent systemic autoimmunity. However, mechanisms that sustain self-tolerance are poorly understood. Here we show that systemic administration of apoptotic cells to mice induced splenic expression of the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO). IDO expression was confined to the splenic marginal zone and was abrogated by depletion of CD169(+) cells. Pharmacologic inhibition of IDO skewed the immune response to apoptotic cells, resulting in increased proinflammatory cytokine production and increased effector T-cell responses toward apoptotic cell-associated antigens. Presymptomatic lupus-prone MRL(lpr/lpr) mice exhibited abnormal elevated IDO expression in the marginal zone and red pulp and inhibition of IDO markedly accelerated disease progression. Moreover, chronic exposure of IDO-deficient mice to apoptotic cells induced a lupus-like disease with serum autoreactivity to double-stranded DNA associated with renal pathology and increased mortality. Thus, IDO limits innate and adaptive immunity to apoptotic self-antigens and IDO-mediated regulation inhibits inflammatory pathology caused by systemic autoimmune disease.
对凋亡细胞中存在的自身抗原的耐受对于维持免疫稳态和预防全身性自身免疫至关重要。然而，维持自身耐受的机制尚不清楚。在这里，我们表明，向小鼠系统给予凋亡细胞可诱导脾脏表达色氨酸分解酶吲哚胺 2,3-双加氧酶（IDO）。IDO 表达局限于脾脏边缘区，并且在耗尽 CD169(+)细胞后被阻断。IDO 的药理学抑制使免疫反应偏向凋亡细胞，导致促炎细胞因子的产生增加，并增加了针对凋亡细胞相关抗原的效应 T 细胞反应。在出现症状前的狼疮易感 MRL(lpr/lpr)小鼠中，边缘区和红髓中出现异常升高的 IDO 表达，IDO 抑制显著加速疾病进展。此外，IDO 缺陷型小鼠慢性暴露于凋亡细胞会引发狼疮样疾病，伴有与肾脏病理学相关的双链 DNA 自身抗体反应和死亡率增加。因此，IDO 限制了对凋亡自身抗原的固有和适应性免疫，IDO 介导的调节抑制了全身性自身免疫疾病引起的炎症病理。
