IMPACT OF CMV UPON T-CELL AGING AND IMMUNE DEFENSE

描述(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。本课题组最近发现，年轻时感染巨细胞病毒而没有感染其他病毒的老年小鼠，对第三方感染的免疫应答能力存在缺陷，NA�ve T细胞受体(TcR)谱系也发生变化。然而，巨细胞病毒损害NA�ve T细胞反应的确切机制仍不完全清楚。这项建议试图确定持续感染CMV对衰老过程中宿主免疫功能(和寿命)的成本，并开始确定如何干预CMV在衰老过程中的负面影响。终生感染巨细胞病毒可能会对新的免疫反应的发展产生不利影响：(I)通过加速NA�ve T细胞多样性的进一步丧失；以及(Ii)通过膨胀的CV特异性效应记忆(EM)T细胞干扰NA�ve T细胞对新感染的反应。此外，加强对CMV的控制和/或减少CMV特异性EM的积累可能有利于免疫防御。这些目标将评估(I)巨细胞病毒在小鼠T细胞受体(TCR)谱的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细胞对保护性免疫的抑制；以及(Iii)改进的巨细胞病毒控制是否决定了人类对疫苗的免疫应答，

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,