IMPACT OF CMV UPON T-CELL AGING AND IMMUNE DEFENSE

描述（由申请方提供）：巨细胞病毒（CMV）与T细胞老化、免疫力受损、剩余寿命缩短和心血管疾病发病率增加相关。我们的研究小组最近发现，在年轻时感染CMV而不是其他病毒的老年小鼠对第三方感染的免疫反应性存在缺陷，并且幼稚T细胞受体（TCR）库发生了改变。然而，CMV损害幼稚T细胞反应的确切机制仍不完全清楚。该提案旨在定义持续CMV感染对衰老中宿主免疫功能（和寿命）的成本（如果有的话），并开始定义干预衰老中CMV负面影响的方法。终身CMV感染可能会对新的免疫反应的发展产生不利影响（i）通过沉淀幼稚T细胞多样性的额外损失;和（ii）通过膨胀的CV特异性效应记忆（EM）T细胞干扰幼稚T细胞对新感染的反应。此外，CMV的改善控制和/或CMV特异性EM积累的减少可能有益于免疫防御。目的是评估（i）CMV在小鼠T细胞受体（TCR）库收缩和免疫防御中的作用;（ii）CMV和/或CMV特异性T细胞对保护性免疫的抑制;以及（iii）改善的CMV控制是否决定了人类对疫苗接种的免疫应答，

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,