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

肝脏演变机制(S)，以抑制和可能抑制宿主对非致病食物的免疫 抗原。因此，嗜肝病毒如丙型肝炎病毒在肝脏中建立了持续的感染 CD8+T细胞反应受损。NK细胞在肝脏中高度丰富，对病毒具有天然的防御作用。 感染。NK细胞与靶细胞结合后，NK细胞被激活并表达NK 激活/抑制受体以激活NK活性。NK细胞亲密相互作用的信号转导 激活/抑制受体是控制NK活性的关键。据报道，NK细胞扮演着一种 先天免疫与获得性免疫的联系，特别是对肝内CDS*T细胞的调节 在病毒感染期间的反应。 我们最近通过两种不同的途径(即IV和SubQ)建立了一个小鼠模型系统 感染是剖析肝内CD8+T细胞调节机制的重要系统 回应。静脉接种主要将病毒抗原输送到肝脏，而SubQ注射则表达 抗原进入淋巴结内。通过使用这种小鼠模型，我们发现腺病毒的不同途径 感染影响CDS*T细胞反应的大小和效应功能。受损的CDS*T细胞 在IV感染小鼠的肝脏中发现了反应。相比之下，感染SubQ腺病毒的小鼠 感染会产生有效的CDS*T细胞反应。此外，NKG2A*NK细胞和IL-10的产生 静脉注射Ad-LacZ感染的小鼠肝脏中的DC增加。耐人寻味的是，体内NK细胞的消耗 逆转了抗病毒CDS*T细胞反应的失调。 这些结果，再加上肝脏NK细胞的抑制功能，暗示了一种潜在的 NK细胞通过NK-DC串扰抑制CDS*T细胞效应功能的机制在这 我们将表征NK细胞在影响CDS*T细胞反应中的作用，并确定 NK介导的CDS*T细胞效应器功能受损机制这些 研究可能会提供关于NK细胞在生成过程中的调节作用的有用信息 有效的CDS*T细胞反应以及针对病毒的免疫治疗策略的新见解 感染。

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.