IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation
IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation
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DOI：
10.1093/intimm/dxt073
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发表时间：
2014-07-01
影响因子：
4.4
通讯作者：
Prendergast, George C.
中科院分区：
文献类型：
--
作者：
Metz, Richard;Smith, Courtney;Prendergast, George C.
IDO2 与色氨酸分解代谢和免疫有关，但其生理功能尚不清楚。在这里，我们报告了 IDO2 遗传缺陷小鼠的特征，这些小鼠发育正常，但在 IDO 介导的 T 细胞调节和炎症反应方面表现出缺陷。该菌株的构建部分是由于我们发现 Ido1(-/-) 小鼠的巨噬细胞中 IDO2 功能由于信息剪接的改变而减弱，从而产生了功能镶嵌，这对解释 Ido1(-/-) 小鼠的发现有影响。在 Ido2(-/-) 小鼠中，在胚胎发育或造血分化方面没有观察到明显的缺陷，血清中的犬尿氨酸以及幼鼠的脾、淋巴结、腹膜、胸腺和骨髓中的免疫细胞均记录有野生型特征。相反，在免疫刺激后，我们确定 Ido2(-/-) 小鼠中 IDO1 依赖性 T 调节细胞的生成存在缺陷，支持 Ido1-Ido2 遗传相互作用，并确立了 Ido2 在免疫调节中的功能作用。在病理生理学上，Ido1(-/-)和Ido2(-/-)小鼠均表现出皮肤接触超敏反应减少，但机制差异明显，只有Ido2缺陷与免疫调节细胞因子的抑制相关，包括GM-CSF、G-CSF、IFN-γ、TNF-α、IL-6和MCP-1/CCL2。 Ido2(-/-)小鼠的表型与Ido1(-/-)小鼠不同，后者对炎症性皮肤癌的易感性降低，这同样表明了对炎症的不同贡献。总而言之，我们的结果初步了解了 IDO2 的免疫调节作用，揭示了它与 IDO1 的遗传相互作用，并区分了它对炎症的非冗余贡献。
IDO2 is implicated in tryptophan catabolism and immunity but its physiological functions are not well established. Here we report the characterization of mice genetically deficient in IDO2, which develop normally but exhibit defects in IDO-mediated T-cell regulation and inflammatory responses. Construction of this strain was prompted in part by our discovery that IDO2 function is attenuated in macrophages from Ido1(-/-) mice due to altered message splicing, generating a functional mosaic with implications for interpreting findings in Ido1(-/-) mice. No apparent defects were observed in Ido2(-/-) mice in embryonic development or hematopoietic differentiation, with wild-type profiles documented for kynurenine in blood serum and for immune cells in spleen, lymph nodes, peritoneum, thymus and bone marrow of naive mice. In contrast, upon immune stimulation we determined that IDO1-dependent T regulatory cell generation was defective in Ido2(-/-) mice, supporting Ido1-Ido2 genetic interaction and establishing a functional role for Ido2 in immune modulation. Pathophysiologically, both Ido1(-/-) and Ido2(-/-) mice displayed reduced skin contact hypersensitivity responses, but mechanistic distinctions were apparent, with only Ido2 deficiency associated with a suppression of immune regulatory cytokines that included GM-CSF, G-CSF, IFN-gamma, TNF-alpha, IL-6 and MCP-1/CCL2. Different contributions to inflammation were likewise indicated by the finding that Ido2(-/-) mice did not phenocopy Ido1(-/-) mice in the reduced susceptibility of the latter to inflammatory skin cancer. Taken together, our results offer an initial glimpse into immune modulation by IDO2, revealing its genetic interaction with IDO1 and distinguishing its non-redundant contributions to inflammation.