NK and T Cell Control of Cowpox Virus

本项目涉及牛痘病毒（CPXV）的免疫控制，CPXV是医学上重要的正痘病毒属的成员。CPXV引起人畜共患感染，在啮齿动物种群中流行，并且具有最大的免疫逃避基因库。该项目基于已发表的工作和申请人实验室关于小鼠CPXV感染的CD 8 + T和自然杀伤（NK）细胞控制的初步数据。申请人的实验室显示，CPXV编码两个开放阅读框（ORF），其抑制感染细胞上的主要组织相容性复合体（MHC）I类（MHC-I）表达。由于CD 8 + T细胞控制，这些ORF的缺失导致CPXV毒力减弱，这是病毒MHC-I抑制在体内感染中的作用的第一个明确的例子。T细胞引发不受影响，但病毒特异性CD 8 + T细胞效应子应答被MHC-I抑制阻断，为进一步研究病毒特异性CD 8 + T细胞应答提供了机会。此外，申请人的实验室显示，在CPXV感染后，NK细胞被募集到引流LN。他们发现这依赖于干扰素-γ，干扰素-γ诱导趋化因子CXCL 9和CXCL 10以及表达CXCR 3的NK细胞。然而，NK细胞被CPXV抑制产生干扰素-γ。在这个项目中，他们计划进一步研究以下特定目标：1）CD 8 + T细胞对CPXV的反应; 2）NK细胞的CPXV依赖性募集; 3）新的。免疫调节CPXV ORF。正在进行的和计划中的实验将与U19应用程序中的其他主要研究人员合作进行。此外，还计划进行人体过渡性研究。因此，这些研究将为先天和适应性免疫系统如何控制病毒（如CPXV）提供新的见解。

This project deals with immune control of cowpox virus (CPXV), a member ofthe medically important orthopoxvirus genus. CPXV causes zoonotic infections, is endemic in rodent populations, and has the largest repertoire of immune evasion genes. The project is based on published work and preliminary data from the applicant's laboratory on CD8+ T and natural killer (NK) cell control of CPXV infections in mice. The applicant's laboratory showed that CPXV encodes two open reading frames (ORFs) that inhibit major histocompatibility complex (MHC) class I (MHC-I) expression on infected cells. Deletion of these ORFs resulted in attenuated CPXV virulence due to CD8+ T cell control, the first clear-cut example of the role of viral MHC-I inhibition in in vivo infections. T cell priming is not affected but virus-specific CD8+ T cell effector responses are blocked by MHC-I inhibition, providing opportunities for further study of virus-specific CD8+ T cell responses. In addition, the applicant's lab showed that NK cells are recruited to the draining LN following CPXV infection. They showed this was dependent on interferon-gamma which induces the chemokines CXCL9 and CXCL10 and CXCR3-expressing NK cells. However, NK cells are inhibited by CPXV from producing interferon-gamma. In this project, they plan to address the following Specific Aims to further study: 1) CD8+ T cell responses to CPXV; 2) CPXV-dependent recruitment of NK cells; and 3) Novel . immunomodulatory CPXV ORFs. Ongoing and planned experiments will be done in collaboration with other principal investigators in this U19 application. In addition, human transiational studies are planned. Thus, these studies will provide new insight into how the innate and adaptive immune systems control viruses, such as CPXV.