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

项目总结/摘要 乔治·C王，医学博士，是约翰霍普金斯大学老年医学部的医学讲师。 霍普金斯大学医学院。作为一名独立的临床研究者，他的长期职业目标是 促进对衰老免疫系统的理解，并通过以下方式改善老年人的生活质量 改进疫苗接种和免疫战略。在接下来的五年职业生涯中， 他的目标是掌握基于四聚体的病原体特异性CD8 + T细胞应答计数， T细胞受体（TCR）多样性分析的单细胞方法，掌握流行病学中的技巧， 一项大型前瞻性队列研究中嵌套的纵向数据分析。跨学科导师制 专家组由老龄化，免疫学和流行病学专家组成，并在 诺贝尔奖获得者和T细胞病毒免疫专家彼得·多尔蒂博士在圣裘德的免疫学实验室 儿童研究医院，将确保实现他的目标。 CD8+克隆T细胞的衰老相关积累，其中很大一部分是特异性的， 据推测，巨细胞病毒（CMV）是一种与老年人虚弱有关的感染， 降低整体TCR多样性，并削弱老年人对感染产生反应的能力。小 已知CMV特异性记忆T细胞和TCR多样性维持的纵向过程， 以及它对衰老免疫系统的免疫能力的影响，并最终对 人类脆弱的发展。在具体目标1中，王博士建议确定纵向轨迹 在5个不同的时间点，记忆性CD8 + T细胞的CMV特异性频率和TCR多样性的模式 在12年的时间里，使用来自美国的储存库外周血单核细胞（PBMC）标本， 妇女健康与老龄化研究（WHAS）II。在具体目标2中，他建议纵向确定 抗CMV感染的免疫应答对CD8 + T细胞对流感免疫潜力的影响，a 对比急性感染与周期性抗原加强，通过检查纵向轨迹模式， 流感特异性记忆CD8 + T细胞的频率和TCR多样性，在5个不同的时间点，超过一个 12-年内，在WHAS II。在具体目标3中，他建议确定 CMV诱导的T细胞克隆性扩增和TCR多样性限制的程度以及CMV感染的发生和演变 在WHAS II中的脆弱性。这些研究的结果将大大提高对长期记忆的理解 T细胞在衰老免疫系统中的维持，并提供了衰老免疫系统的机制和流行病学证据。 CMV感染和限制性TCR多样性在获得性免疫潜能降低的发病机制中的作用， 感染性病原体和老年人的虚弱。这项研究计划的长期目标是使 及早查明使老年人最易受感染的宿主因素和环境暴露 对健康不利的结果和脆弱性进行预防和治疗，以便及早采取预防和治疗措施。

Project Summary/Abstract 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.