Regulation of CD8+ T cell responses via liver NK-DC crosstalk

通过肝脏 NK-DC 串扰调节 CD8 T 细胞反应

• 批准号: 7746094
• 负责人: Young S. Hahn
• 金额: $ 25.51万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-18 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7746094
• 关键词: Adenovirus Infections; Adenoviruses; Affect; Antigens; Antiviral Agents; Biological Models; Bone Marrow; CD8B1 gene; Cell physiology; Cells; Chimera organism; Coupled; Failure; Food; Generations; Goals; Hepatitis C virus; Hepatocyte; IL2RA gene; Immune; Immune response; Immunity; Immunization; Immunotherapeutic agent; Impairment; Infection; Injection of therapeutic agent; Injury; Interleukin-10; LacZ Genes; Link; Liver; Mediating; Modeling; Mus; Natural Immunity; Natural Killer Cells; Phase; Play; Poly I-C; Recruitment Activity; Regulation; Reporter; Reporting; Role; Route; Signal Transduction; Site; System; T cell regulation; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic Agents; Tissues; Viral Antigens; Virus; Virus Diseases; base; cell type; cytokine; design; in vivo; insight; intrahepatic; liver function; liver infection; lymph nodes; receptor; response

The liver evolves mechanism(s) to dampen and possibly suppress the host immunity to nonpathogenic food antigens. As a result, liver tropic viruses such as HCV establish the persistent infection in the liver due impaired CD8+ T cell responses. NK cells are highly enriched in the liver and act as innate defense to viral infection. Following conjugation between NK cells and target cells, NK cells are activated and express NK activating/inhibitory receptors to trigger NK activity. Signaling through intimate interaction of NK activation/inhibitory receptors is critical for controlling NK activities. NK cells have been reported to play a pivotal role in linking innate immunity to adaptive immunity, particularly regulation of intrahepatic CDS* T cell responses during viral infection. We have recently established a murine model system via two different routes (i.e. IV vs SubQ) of adenovirus infection, which is an important system to dissect the mechanism for regulation of intrahepatic CD8+ T cell responses. IV inoculation predominantly delivers viral antigen to the liver while SubQ injection expresses antigen into the lymph nodes. By employing this murine model, we found that different route of adenovirus infection influence the magnitude and effector function of CDS* T cell responses. The impaired CDS* T cell responses were found in the liver of mice following IV infection. In contrast, mice infected SubQ adenovirus infection generates the effective CDS* T cell responses. In addition, NKG2A*NK cells and IL-10-producing DC are increased in the liver from IV Ad-LacZ infected mice. Intriguingly, the in vivo depletion of NK cells reversed the dysregulation of antiviral CDS* T cell responses. These results, coupled with evidence that the inhibitory function of liver NK cells, suggest a potential mechanism for NK cell-mediated in inhibition of CDS* T cell effector function via NK-DC cross-talk. In this proposal, we will characterize the effect of NK cells on affecting CDS* T cell responses and determine the mechanism for NK-mediated impairment of CDS* T cell effector function via altering DC activation. These studies may provide a useful information regarding the regulatory role of NK cell dysregulation in generation of effective CDS* T cell responses as well as new insights for immunotherapeutic strategies against viral infection.

肝脏进化出一种机制来抑制宿主对非致病性食物的免疫力 抗原因此，嗜肝病毒如HCV在肝脏中建立持续感染， 受损的CD 8 + T细胞应答。NK细胞在肝脏中高度富集，并充当对病毒的先天防御。 感染在NK细胞和靶细胞之间接合之后，NK细胞被激活并表达NK细胞。 激活/抑制受体以触发NK活性。通过NK的密切相互作用的信号传导 活化/抑制受体对于控制NK活性至关重要。据报道，NK细胞发挥了 在连接先天性免疫与适应性免疫，特别是调节肝内CDS* T细胞中的关键作用 病毒感染时的反应。 我们最近通过两种不同的腺病毒途径（即IV与SubQ）建立了小鼠模型系统 感染是研究肝内CD 8 + T细胞调节机制的重要系统 应答IV接种主要将病毒抗原递送至肝脏，而SubQ注射表达 抗原进入淋巴结。通过使用这种小鼠模型，我们发现不同途径的腺病毒 感染影响CDS* T细胞应答的幅度和效应子功能。受损的CDS* T细胞 在IV感染后小鼠的肝脏中发现了应答。相反，小鼠感染SubQ腺病毒， 感染产生有效的CDS* T细胞应答。此外，NKG 2A *NK细胞和产生IL-10的 DC在IV Ad-LacZ感染小鼠的肝脏中增加。有趣的是，体内NK细胞的消耗 逆转了抗病毒CDS* T细胞应答的失调。 这些结果，再加上证据表明，肝脏NK细胞的抑制功能，表明一个潜在的 NK细胞介导的通过NK-DC串扰抑制CDS* T细胞效应子功能的机制。在这 我们将描述NK细胞对影响CDS* T细胞应答的作用，并确定NK细胞对CDS* T细胞应答的影响。 NK介导的CDS* T细胞效应子功能受损的机制通过改变DC活化。这些 研究可能会提供一个有用的信息，关于NK细胞失调的调节作用， 有效的CDS* T细胞反应以及针对病毒的免疫策略的新见解 感染