IMPACT OF CMV UPON T-CELL AGING AND IMMUNE DEFENSE

描述（由申请人提供）：巨细胞病毒（CMV）与t细胞老化、免疫功能受损、剩余寿命缩短和心血管疾病发病率增加有关。我们的研究小组最近发现，年轻时感染巨细胞病毒（CMV）而不是其他病毒的老年小鼠，对第三方感染表现出免疫反应缺陷，并且幼稚T细胞受体（TCR）库发生改变。然而，CMV损害幼稚T细胞反应的确切机制仍不完全清楚。本研究旨在确定持续巨细胞病毒感染对衰老过程中宿主免疫功能（和寿命）的影响（如果有的话），并开始确定干预巨细胞病毒在衰老过程中负面影响的方法。终生巨细胞病毒感染可能对新免疫反应的发展产生不利影响：(1)通过加速初始T细胞多样性的额外损失；（ii）通过膨胀的、cv特异性效应记忆（EM） T细胞与原始T细胞对新感染的反应的干扰。此外，改善对巨细胞病毒的控制和/或减少巨细胞病毒特异性EM的积累可能有利于免疫防御。目的是评估(i)巨细胞病毒在小鼠T细胞受体（TCR）库收缩和免疫防御中的作用；（ii）巨细胞病毒和/或巨细胞病毒特异性T细胞抑制保护性免疫；（iii） CMV控制的改善是否决定了人对疫苗的免疫反应；

DESCRIPTION (provided by applicant): The cytomegalovirus (CMV) has been associated to T-cell aging, impaired immunity, reduced residual lifespan and increased morbidity of cardiovascular diseases. It was recently shown by our group that old mice, infected in youth with CMV, but not other viruses, exhibit defects in immune responsiveness to third-party infections, and alterations in na�ve T cell receptor (TCR) repertoire. Yet, the precise mechanism by which CMV impairs na�ve T cell responses remains incompletely understood. This proposal seeks to define the cost, if any, of persistent CMV infection on host immune function (and lifespan) in aging and to begin to define ways to intervene against negative effects of CMV in aging. Lifelong CMV infection could adversely impact the development of new immune responses (i) by precipitating additional loss of na�ve T cell diversity; and (ii) by interference of inflated, CV-specific effector memory (EM) T cells with na�ve T cell responses against new infection. Further, improved control of CMV and/or reduction of CMV-specific EM accumulation could be beneficial for immune defense. The aims will assess (i) the role of CMV in constriction of T cell receptor (TCR) repertoire and immune defense in mice; (ii) Inhibition of protective immunity by CMV and/or by CMV-specific T cells; and (iii) whether improved CMV control determine human immune responsiveness to vaccination,