CMV infection and T-cell receptor diversity in the pathogenesis of frailty

描述（由申请人提供）：乔治C。王博士是约翰霍普金斯大学医学院老年医学系的医学讲师。作为一名独立的临床研究者，他的长期职业目标是通过改进疫苗接种和免疫策略，促进对衰老免疫系统的理解，提高老年人的生活质量。在未来五年的职业发展中，他的目标是掌握病原体特异性CD8+ T细胞反应的四聚体计数和T细胞受体（TCR）多样性分析的单细胞方法，并掌握大型前瞻性队列研究中嵌套的纵向数据分析的流行病学技能。一个由衰老、免疫学和流行病学专家组成的跨学科导师小组，以及在圣裘德儿童研究医院的诺贝尔奖获得者和T细胞病毒免疫专家彼得·多尔蒂博士免疫学实验室进行的高级校外培训，将确保实现他的目标。 CD8+克隆T细胞的衰老相关积累，其中很大一部分对巨细胞病毒（CMV）具有特异性，巨细胞病毒（CMV）是一种与老年人虚弱相关的感染，已被推测会降低整体TCR多样性并损害老年人对感染的反应能力。关于CMV特异性记忆T细胞和TCR多样性维持的纵向过程及其对衰老免疫系统的免疫能力和最终对人类虚弱发展的影响知之甚少。在具体目标1中，王博士提出使用来自妇女健康与衰老研究（WHAS）II的储存库外周血单核细胞（PBMC）标本，在12年期间的5个不同时间点确定记忆CD8+ T细胞和TCR多样性的CMV特异性频率的纵向轨迹模式。在具体目标2中，他提出通过检查WHAS II中12年期间5个不同时间点的记忆性CD8 + T细胞和TCR多样性的流感特异性频率的纵向轨迹模式，纵向确定针对CMV感染的免疫应答对CD8+ T细胞对流感免疫的潜力的影响，这是一种对比急性感染与周期性抗原加强。在具体目标3中，他提出确定CMV诱导的T细胞克隆扩增和TCR多样性限制程度之间的时间关系以及WHAS II中虚弱的发作和演变。这些研究的结果将大大提高对衰老免疫系统中长期记忆T细胞维持的理解，并提供CMV感染和限制TCR多样性在老年人对感染性病原体的适应性免疫潜力降低和虚弱的发病机制中的作用的机制和流行病学证据。这项研究计划的长期目标是能够及早确定使老年人最容易受到不利健康结果和虚弱影响的宿主因素和环境暴露，以便及早采取预防和治疗干预措施。 公共卫生相关性：这项研究将提高我们对免疫系统中的记忆是如何对抗病毒感染的理解，以及免疫系统的负面变化是否会增加老年人虚弱的风险。鉴于巨细胞病毒的高流行率，更好地理解和认识这种病毒对免疫系统能力降低和脆弱性的贡献具有重要的公共卫生意义。

DESCRIPTION (provided by applicant): George C. Wang, MD, is an Instructor of Medicine in the Division of Geriatric Medicine at the Johns Hopkins University School of Medicine. His long-term career goal, as an independent clinical investigator, is to advance the understanding of the aging immune system and improve older adults' quality of life through improved vaccination and immunotherapeutic strategies. During the next five years of his career development, he aims to acquire mastery in tetramer-based enumeration of pathogen-specific CD8+ T-cell responses and the single-cell method of T-cell receptor (TCR) diversity analysis, and master epidemiologic skills in the analysis of longitudinal data nested within a large prospective cohort study. An interdisciplinary mentorship panel consisting of experts in aging, immunology, and epidemiology, and advanced extramural training in the immunology laboratory of Dr. Peter Doherty, Nobel laureate and T-cell viral immunity expert, at St. Jude Children's Research Hospital, will ensure the achievement of his goals. The aging-related accumulation of CD8+ clonal T cells, a significant proportion of which are specific for cytomegalovirus (CMV), an infection that has been associated with frailty in older adults, has been speculated to reduce overall TCR diversity and impairing the ability of older adults to mount responses to infections. Little is known about the longitudinal course of CMV-specific memory T cell and TCR diversity maintenance in humans, and its effect on the immune competence of the aging immune system and ultimately on the development of frailty in humans. In Specific Aim 1, Dr. Wang proposes to determine the longitudinal trajectory pattern of the CMV-specific frequencies of memory CD8+ T cells and TCR diversity at 5 distinct time points over a 12-year period, using repository peripheral blood mononuclear cell (PBMC) specimens from the Women's Health and Aging Study (WHAS) II. In Specific Aim 2, he proposes to determine longitudinally the effect of the immune response against CMV infection on the potential of CD8+ T-cell immunity to influenza, a contrasting acute infection with periodic antigenic boosting, by examining the longitudinal trajectory pattern of the influenza-specific frequencies of memory CD8+ T cells and TCR diversity, at 5 distinct time points over a 12-year period in WHAS II. In Specific Aim 3, he proposes to determine the temporal relationship between CMV-induced T-cell clonal expansions and degree of TCR diversity restriction and the onset and evolution of frailty in WHAS II. Results from these studies will substantially improve the understanding of long-term memory T cell maintenance in the aging immune system, and provide mechanistic and epidemiologic evidence of the role of CMV infection and restricted TCR diversity in the pathogenesis of reduced adaptive immune potential to infectious pathogens and of frailty in older adults. The long-term objective of this research plan is to enable the early identification of host factors and environmental exposures that render older adults most vulnerable to adverse health outcomes and frailty so that early preventative and therapeutic interventions can be instituted. PUBLIC HEALTH RELEVANCE: This research will improve our understanding of how memory in the immune system is maintained against viral infections and whether negative changes in the immune system increase the risk for frailty in older adults. Given the high prevalence of cytomegalovirus, a better understanding and recognition this virus's contribution to reduced immune system capacity and frailty is of significance public health importance.