Tissue-Resident Memory CD8+T Cells Acting as Mediators of Salivary Gland Damage in a Murine Model of Sjogren's Syndrome
Tissue-Resident Memory CD8+T Cells Acting as Mediators of Salivary Gland Damage in a Murine Model of Sjogren's Syndrome
复制标题
组织驻留记忆 CD8 T 细胞在干燥综合征小鼠模型中充当唾液腺损伤的介质
DOI：
10.1002/art.40676
复制
发表时间：
2019-01-01
影响因子：
13.3
通讯作者：
Lian, Zhe-Xiong
中科院分区：
文献类型：
--
作者：
Gao, Cai-Yue;Yao, Yuan;Lian, Zhe-Xiong
目的虽然CD 4 + T细胞在干燥综合征（SS）发病中的作用已被证实，但CD 8 + T细胞的致病意义尚不清楚。本研究旨在探讨CD 8 + T细胞在SS发生发展中的作用。方法应用流式细胞术和免疫荧光技术检测原发性SS患者唇腺内T细胞浸润情况。平行地，使用p40（-/-）CD 25（-/-）小鼠作为SS的鼠模型。此外，将CD 4、CD 8a或干扰素-γ（IFN-γ）基因敲除的小鼠与p40（-/-）CD 25（-/-）小鼠杂交，以研究特定谱系亚群的致病意义，包括功能性唾液腺试验以及组织病理学和血清学数据。在该小鼠SS模型中使用CD 8 + T细胞特异性耗竭抗体以评估其作为治疗策略的潜力。结果SS患者唇腺中具有组织驻留记忆表型的CD 8 + T细胞明显多于CD 4 + T细胞，主要与涎腺导管上皮细胞和腺泡细胞共定位。此外，在该小鼠SS模型中，具有CD 69 + CD 103 +/-组织驻留表型和IFN γ产生显著升高的浸润性CD 8 + T细胞在小鼠下颌下腺中占主导地位。CD 8a基因敲除消除了这些小鼠中SS的发展。IFN γ的敲除减少了CD 8 + T细胞浸润和腺体破坏。更重要的是，CD 8 + T细胞的耗竭完全保护小鼠免受SS的病理表现，甚至在疾病发作后。结论CD 8 + T细胞在唾液腺SS的发生、发展中具有重要的病理意义。针对CD 8 + T细胞的治疗可能是治疗人类受试者SS的合理疗法。
Objective Although a role for CD4+ T cells in the pathogenesis of Sjogren's syndrome (SS) has been documented, the pathogenic significance of CD8+ T cells is unclear. The aim of this study was to investigate the role of CD8+ T cells in the development of SS. Methods Flow cytometry and immunofluorescence analyses were utilized to detect T cell infiltration within the labial salivary glands of patients with primary SS. In parallel, p40(-/-)CD25(-/-) mice were used as a murine model of SS. In addition, mice with genetic knockout of CD4, CD8a, or interferon-gamma (IFN gamma) were crossed with p40(-/-)CD25(-/-) mice to study the pathogenic significance of specific lineage subpopulations, including functional salivary gland tests as well as histopathologic and serologic data. A CD8+ T cell-specific depletion antibody was used in this murine SS model to evaluate its potential as a therapeutic strategy. Results CD8+ T cells with a tissue-resident memory phenotype outnumbered CD4+ T cells in the labial salivary glands of patients with SS, and were primarily colocalized with salivary duct epithelial cells and acinar cells. Furthermore, infiltrating CD8+ T cells with a CD69+CD103+/- tissue-resident phenotype and with a significant elevation of IFN gamma production were dominant in the submandibular glands of mice in this murine SS model. CD8a knockout abrogated the development of SS in these mice. Knockout of IFN gamma decreased CD8+ T cell infiltration and gland destruction. More importantly, depletion of CD8+ T cells fully protected mice against the pathologic manifestations of SS, even after the onset of disease. Conclusion These data reveal the pathogenic significance of CD8+ T cells in the development and progression of SS in the salivary glands. Treatment directed against CD8+ T cells may be a rational therapy for the management of SS in human subjects.