Critical role for CD1d-restricted invariant NKT cells in stimulating intrahepatic CD8 T-cell responses to liver antigen.
Critical role for CD1d-restricted invariant NKT cells in stimulating intrahepatic CD8 T-cell responses to liver antigen.
复制标题
CD1d 限制的不变 NKT 细胞在刺激肝内 CD8 T 细胞对肝抗原反应中的关键作用。
DOI：
10.1053/j.gastro.2008.02.037
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发表时间：
2008
期刊：
影响因子：
29.4
通讯作者：
Boes,Marianne
中科院分区：
文献类型：
--
作者：
Sprengers,Dave;Sillé,FennaCM;Derkow,Katja;Besra,GurdyalS;Janssen,HarryLA;Schott,Eckart;Boes,Marianne
背景和目的Vα14 不变自然杀伤 T 细胞 (iNKT) 位于肝脏等外周组织中，而不是淋巴组织中。因此，它们在调节传统主要组织相容性复合体 (MHC) 限制性 T 细胞反应刺激中的作用仍然不明确。我们在这里使用转铁蛋白-mOVA (Tf-mOVA) 小鼠描述了 Vα14 iNKT 细胞在调节传统 T 细胞对肝脏中表达的抗原的反应中的作用。方法在存在或不存在 iNKT 细胞激动剂的情况下，将幼稚卵清蛋白特异性 I 类 MHC 限制性 T 细胞 (OTI) 过继转移到 Tf-mOVA 小鼠中 α-半乳糖神经酰胺，然后分析 OTI T 细胞启动、抗原特异性细胞因子的产生、细胞毒性杀伤能力和肝损伤。结果 OTI 细胞的转移导致肝内 T 细胞的强劲抗原特异性增殖。在肝脏中激活 OTI T 细胞，并通过使用 α-半乳糖神经酰胺共激活 Vα14 iNKT 细胞来刺激抗原特异性效应器功能。这种刺激在缺乏 Vα14 iNKT 细胞的 CD1d−/−Tf-mOVA 小鼠中不存在，并且当 Vα14 iNKT 细胞产生干扰素-γ 和肿瘤坏死因子-α 被阻断时，这种刺激就会被阻止。结论 CD1d 限制的 Vα14 iNKT 细胞刺激肝内 CD8 T 细胞效应器对肝脏表达的抗原的反应。我们的研究结果阐明了针对自身免疫性和可能的传染性肝病的靶向免疫治疗的先前未知的干预点。
Background & AimsVα14 invariant natural killer T cells (iNKT) are localized in peripheral tissues such as the liver rather than lymphoid tissues. Therefore, their role in modulating the stimulation of conventional, major histocompatibility complex (MHC)-restricted T-cell responses has remained ambiguous. We here describe a role for Vα14 iNKT cells in modulating conventional T-cell responses to antigen expressed in liver, using transferrin-mOVA (Tf-mOVA) mice.MethodsNaïve ovalbumin-specific class I MHC-restricted T cells (OTI) were adoptively transferred into Tf-mOVA mice in the presence or absence of iNKT-cell agonist α-galactosylceramide, after which OTI T-cell priming, antigen-specific cytokine production, cytotoxic killing ability, and liver damage were analyzed.ResultsTransfer of OTI cells resulted in robust intrahepatic, antigen-specific proliferation of T cells. OTI T cells were activated in liver, and antigen-specific effector function was stimulated by coactivation of Vα14 iNKT cells using α-galactosylceramide. This stimulation was absent in CD1d−/−Tf-mOVA mice, which lack Vα14 iNKT cells, and was prevented when interferon-γ and tumor necrosis factor-α production by Vα14 iNKT cells was blocked.ConclusionsCD1d-restricted Vα14 iNKT cells stimulate intrahepatic CD8 T-cell effector responses to antigen expressed in liver. Our findings elucidate a previously unknown intervention point for targeted immunotherapy to autoimmune and possibly infectious liver diseases.