Hsu Willy, Zhang Weici, Tsuneyama Koichi, Moritoki Yuki, Ridgway William M, Ansari Aftab A, Coppel Ross L, Lian Zhe-Xiong, Mackay Ian, Gershwin M Eric
Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA 95616, USA.
Hepatology. 2009 Jan;49(1):133-40. doi: 10.1002/hep.22591.
Interleukin-2 (IL-2) receptor alpha knockout (IL-2Ralpha(-/-)) mice have a deficiency of CD25 and a corresponding functional defect in T regulatory cells (Tregs). These mice spontaneously develop portal inflammation with biliary ductular damage and colitis with features similar to human inflammatory bowel disease with T cell infiltrates in both the liver and colon. In humans, inflammatory bowel disease may be accompanied by primary sclerosing cholangitis (PSC), but seldom primary biliary cirrhosis (PBC). We hypothesized that the effector mechanism responsible for T cell infiltrates would differ for colon versus liver. To address this thesis, we developed three colonies of double-knockout mice including IL-2Ralpha(-/-) CD4(-/-), IL-2Ralpha(-/-) CD8(-/-), and IL-2Ralpha(-/-) T cell receptor (TCR)-beta(-/-). Tissue immunopathology, body weight, and serum levels of cytokines, immunoglobulins, and anti-mitochondrial antibodies (AMA) were assayed at 3 months of age. Relative to IL-2Ralpha(-/-) mice, IL-2Ralpha(-/-) CD4(-/-) mice had increased biliary ductular damage but reduced inflammation in the colon. In contrast, IL-2Ralpha(-/-) CD8(-/-) mice had increased colon inflammation but markedly attenuated biliary ductular damage. Both IL-2Ralpha(-/-) CD4(-/-) and IL-2Ralpha(-/-) CD8(-/-) mice demonstrated elevated serum levels of tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), interleukin-12p40 (IL-12p40), and interleukin-2 (IL-2) compared with C57BL/6J controls, but only IL-2Ralpha(-/-) CD8(-/-) mice had increased serum levels of immunoglobulin A (IgA), AMA and interleukin-17 (IL-17). Finally, and of importance, IL-2Ralpha(-/-) TCR-beta(-/-) mice had abrogation of liver and colon pathological conditions and lacked AMA. In conclusion, on loss of Treg function in mice, CD8 T cells mediate biliary ductular damage whereas CD4 T cells mediate induction of colon-specific autoimmunity.
白细胞介素-2（IL-2）受体α基因敲除（IL-2Rα(-/-)）小鼠存在CD25缺陷以及相应的调节性T细胞（Tregs）功能缺陷。这些小鼠会自发出现伴有胆管损伤的门静脉炎症以及类似于人类炎症性肠病的结肠炎，肝脏和结肠均有T细胞浸润。在人类中，炎症性肠病可能伴有原发性硬化性胆管炎（PSC），但很少伴有原发性胆汁性肝硬化（PBC）。我们推测，导致T细胞浸润的效应机制在结肠和肝脏中会有所不同。为了验证这一论点，我们培育了三个双基因敲除小鼠品系，包括IL-2Rα(-/-) CD4(-/-)、IL-2Rα(-/-) CD8(-/-)和IL-2Rα(-/-) T细胞受体（TCR）-β(-/-)。在3月龄时检测组织免疫病理学、体重以及细胞因子、免疫球蛋白和抗线粒体抗体（AMA）的血清水平。相对于IL-2Rα(-/-)小鼠，IL-2Rα(-/-) CD4(-/-)小鼠的胆管损伤增加，但结肠炎症减轻。相比之下，IL-2Rα(-/-) CD8(-/-)小鼠的结肠炎症增加，但胆管损伤明显减轻。与C57BL/6J对照相比，IL-2Rα(-/-) CD4(-/-)和IL-2Rα(-/-) CD8(-/-)小鼠的血清肿瘤坏死因子α（TNF-α）、干扰素γ（IFN-γ）、白细胞介素-12p40（IL-12p40）和白细胞介素-2（IL-2）水平均升高，但只有IL-2Rα(-/-) CD8(-/-)小鼠的血清免疫球蛋白A（IgA）、AMA和白细胞介素-17（IL-17）水平升高。最后且重要的是，IL-2Rα(-/-) TCR-β(-/-)小鼠的肝脏和结肠病理状况消失且无AMA。总之，在小鼠Treg功能丧失时，CD8 T细胞介导胆管损伤，而CD4 T细胞介导结肠特异性自身免疫的诱导。
