Division of Gastroenterology and HepatologyKey Laboratory of Gastroenterology and HepatologyMinistry of HealthState Key Laboratory for Oncogenes and Related GenesRenji HospitalShanghai Institute of Digestive DiseaseSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina.
Chronic Disease LaboratoryInstitutes for Life Sciences and School of MedicineSouth China University of TechnologyGuangzhouChina.
Hepatology. 2021 Aug;74(2):847-863. doi: 10.1002/hep.31739. Epub 2021 Jun 22.
The diverse inflammatory response found in the liver of patients with autoimmune hepatitis (AIH) is well established, but identification of potentially pathogenic subpopulations has proven enigmatic.
We report herein that CD69 CD103 CD8 tissue-resident memory T cells (T ) are significantly increased in the liver of patients with AIH compared to chronic hepatitis B, NAFLD, and healthy control tissues. In addition, there was a significant statistical correlation between elevation of CD8 T cells and AIH disease severity. Indeed, in patients with successful responses to immunosuppression, the frequencies of such hepatic CD8 T cells decreased significantly. CD69 CD8 and CD69 CD103 CD8 T cells, also known as CD8 T cells, reflect tissue residency and are well known to provide intense immune antigenic responses. Hence, it was particularly interesting that patients with AIH also manifest an elevated expression of IL-15 and TGF-β on inflammatory cells, and extensive hepatic expression of E-cadherin; these factors likely contribute to the development and localization of CD8 T cells. Based on these data and, in particular, the relationships between disease severity and CD8 T cells, we studied the mechanisms involved with glucocorticoid (GC) modulation of CD8 T cell expansion. Our data reflect that GCs in vitro inhibit the expansion of CD8 T cells induced by IL-15 and TGF-β and with direct down-regulation of the nuclear factor Blimp1 of CD8 T cells.
Our data suggest that CD8 T cells play a critical role in the pathogenesis of AIH, and GCs attenuate hepatic inflammation through direct inhibition of CD8 T cell expansion.
自身免疫性肝炎（AIH）患者肝脏中存在多种炎症反应，这一点已得到充分证实，但确定潜在的致病亚群一直是个谜。
我们在此报告，与慢性乙型肝炎、非酒精性脂肪性肝病和健康对照组织相比，AIH 患者肝组织中 CD69 CD103 CD8 组织驻留记忆 T 细胞（T 细胞）显著增加。此外，CD8 T 细胞升高与 AIH 疾病严重程度之间存在显著的统计学相关性。事实上，在对免疫抑制有成功反应的患者中，这些肝 CD8 T 细胞的频率显著降低。CD69 CD8 和 CD69 CD103 CD8 T 细胞，也称为 CD8 T 细胞，反映了组织驻留性，并且众所周知，它们可以提供强烈的免疫抗原反应。因此，特别有趣的是，AIH 患者还表现出炎症细胞中 IL-15 和 TGF-β的表达升高，以及广泛的肝 E-钙粘蛋白表达；这些因素可能有助于 CD8 T 细胞的发展和定位。基于这些数据，特别是疾病严重程度与 CD8 T 细胞之间的关系，我们研究了糖皮质激素（GC）调节 CD8 T 细胞扩增的机制。我们的数据反映，GC 在体外抑制由 IL-15 和 TGF-β诱导的 CD8 T 细胞扩增，并通过直接下调 CD8 T 细胞的核因子 Blimp1 来实现。
我们的数据表明，CD8 T 细胞在 AIH 的发病机制中起关键作用，GC 通过直接抑制 CD8 T 细胞扩增来减轻肝炎症。
