KSHV REGULATION OF INNATE CYTOKINE RESPONSES AND T CELL ACTIVATION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，不一定是研究者的机构。 背景 卡波西肉瘤相关疱疹病毒（KSHV）是卡波西肉瘤（KS）的病原体。现有的数据表明，T细胞应答对于KS进展的控制是至关重要的，并且抗原呈递细胞（APC）为产生这些应答提供重要的激活信号。KSHV感染APC是否损害有效的T细胞应答从而促进KS进展尚不清楚。我们的模型系统表明，KSHV通过多种KSHV编码的机制，涉及APC的感染，包括APC细胞因子的产生改变，损害T细胞活化。因此，我们建议使用这些系统，包括来自人类患者的原代细胞，以确定KSHV调节APC功能和T细胞活化的机制。 理由 KSHV是最常见的癌症原因，特别是在艾滋病毒感染患者中出现的口腔癌。口服KS对现有疗法有抵抗力，并预示着不祥的预后。更好地了解KSHV如何通过感染APC调节T细胞活化，可能为开发基于免疫或抗炎的策略来治疗或预防口腔KS提供新的机会。 研究设计和结局指标 使用人类和小鼠APC作为KSHV感染和细胞培养中基因转移的靶点，我们将首先鉴定出参与APC分泌免疫抑制分子（包括IL-6、IL-10和活性氮类（RNS））的特定KSHV编码基因。接下来，使用抗原非依赖性和抗原依赖性T细胞活化测定，我们将测试减少KSHV感染的APC分泌IL-6、IL-10和RNS并在此环境中恢复T细胞活化的干预策略。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background The Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS). Existing data suggest that T cell responses are critical for the control of KS progression, and antigen-presenting cells (APC) provide important activation signals for generating these responses. Whether KSHV infection of APC impairs effective T cell responses thereby promoting KS progression is unknown. Our model systems show that KSHV impairs T cell activation through multiple KSHV-encoded mechanisms involving infection of APC, including alteration of cytokine production by APC. Therefore, we propose to use these systems, including primary cells from human patients, to identify mechanisms for KSHV regulation of APC function and T cell activation. Rationale KSHV is the most common cause of cancer, and specifically oral cancers, arising in HIV-infected patients. Oral KS is resistant to existing therapies and portends an ominous prognosis. A better understanding of how KSHV regulates T cell activation through the infection of APC may provide new opportunites for developing immune-based or anti-inflammatory strategies for the treatment or prevention of oral KS. Study design and outcome measures Using human and murine APC as targets of KSHV infection and gene transfer in cell culture, we will first identify specific KSHV-encoded genes involved in APC secretion of immunoinhibitory molecules, including IL-6, IL-10, and reactive nitrogen species (RNS). Next, using antigen-independent and antigen-dependent T cell activation assays, we will test interventional strategies for reducing IL-6, IL-10, and RNS secretion by KSHV-infected APC and restoring T cell activation in this environment.