In Vivo Analysis of T lymphocytes in the Persistently Infected CNS

描述(申请人提供)：中枢神经系统(CMS)对免疫系统构成了一个独特的挑战，因为它被认为是一个免疫专门化的隔室，位于无窗屏障后面，显著限制了抗原呈递机制的表达。由于中枢神经系统是分区的，并对适应性免疫系统施加了严格的调节机制，因此感染人类的多种病原体(如艾滋病毒、疱疹病毒、麻疹病毒、HTLV-1、JC病毒等)。能够在中枢神经系统中建立持久性。这些持续感染会导致严重的行为改变和神经功能障碍，对人类健康造成不利影响。进入中枢神经系统的持续性感染通常首先在外围建立持久性。因此，这种常见的情况向生物医学研究人员提出了从外围和中枢神经系统根除病原体的挑战。鉴于中枢神经系统为寻求持久性的病毒提供了如此有利的环境，我们推测，从这个专门的隔室获得清除将比从周围组织清除更具挑战性。这项拟议的研究将探索一种小鼠模型系统，在该系统中，免疫抑制病毒通过外周途径进入，然后在中枢神经系统建立长期的持久性，尽管最终从外周清除。从外周清除病毒恰好与病毒特异性T细胞的功能重新激活(我们希望在人类身上实现这种情况)相吻合，但这种反应无法阻止病毒在中枢神经系统内的长期存在。重要的是，在中枢神经系统病毒感染的高峰期给予外源记忆T淋巴细胞可以有效地清除病毒从外周和中枢神经系统。因此，即使内源性免疫反应不充分，过继转移的记忆T淋巴细胞群体仍能成功清除。这项拟议的研究旨在通过确定内源性T细胞反应的缺陷(特定目标1)和高度成功的采用反应的操作方式(特定目标2)，显著促进我们对中枢神经系统持续病毒感染的T细胞免疫的理解。这项研究的主要目的是机械地定义导致CNS病毒清除成功的因素，以便我们能够更好地补充失败的(或不足的)内源性反应。

DESCRIPTION (provided by applicant): The central nervous system (CMS) poses a unique challenge to the immune system, as it is considered an immunologically specialized compartment that resides behind a non-fenestrated barrier and significantly limits the expression of antigen-presenting machinery. Because the CNS is compartmentalized and imposes strict regulatory mechanisms on the adaptive immune system, a multitude of pathogens that infect humans (e.g. HIV, herpes virus, measles virus, HTLV-1, JC virus, etc.) are capable of establishing persistence in the CNS. These persistent infections can give rise to severe behavioral alterations and neurological dysfunction, which adversely affects human health. Persistent infections that gain access to the CNS often do so by first establishing persistence in the periphery. This common scenario consequently presents biomedical researchers with the challenge of eradicating the pathogen from both the periphery as well as the CNS. Given that the CNS provides such a favorable environment to viruses seeking persistence, we postulate that achieving clearance from this specialized compartment will be far more challenging than from peripheral tissues. The proposed study will explore a murine model system in which an immunosuppressive virus is introduced through a peripheral route and then establishes prolonged persistence in the CNS despite the eventual clearance from the periphery. Clearance from the periphery coincides with a functional reactivation of virus-specific T cells (a scenario we hope to achieve in humans), yet this response is unable to prevent prolonged viral persistence within the CNS. Importantly, administration of exogenous memory T lymphocytes at the peak of CNS viral infection results in efficient clearance of the virus from both the periphery and the CNS. Thus, an adoptively transferred population of memory T lymphocytes can achieve successful clearance despite an inadequate endogenous immune response. The proposed study is designed to significantly advance our understanding of T cell immunity to persistent viral infections in the CNS by establishing the shortcomings of the endogenous T cell response (Specific Aim#1) and the modus operand of a highly successful adoptive response (Specific Aim#2). The main objective of this research is mechanistically define the factors that give rise to successful CNS viral clearance so that we are better able to supplement a failing (or inadequate) endogenous response.