Mechanisms of thymic stromal-immune crosstalk for homeostasis and naïve T cell licensing across life

数据摘要/摘要 老年人T细胞介导的免疫力低下与以下疾病的发病率和死亡率增加有关： 感染性疾病、次优的癌症免疫力和对疫苗接种的不良反应。T细胞免疫力下降 部分原因是胸腺功能的变化开始于生命的第一个十年， 在成年早期到中期退化。然而，基质免疫串扰如何维持分化的， 胸腺老化过程中的变化，以及 修饰幼稚T细胞的特性知之甚少。科里米勒博士的职业重点是了解 髓质胸腺功能和功能障碍的潜在机制，包括在衰老过程中，以及这些机制是如何发挥作用的。 状态塑造幼稚T细胞发育，目的是为新型免疫恢复疗法提供信息。 他对基质免疫串扰的兴趣始于他作为MD/PhD实习生的博士研究期间，在那里他 研究了T细胞存活细胞因子IL-7的外周来源。完成医学院学业后，他选择了 放弃居住权，支持博士后培训，并专注于上皮异质性内， 胸腺髓质，导致第一作者发表在自然。米勒博士对进一步职业发展的追求 培训是基于他的愿望，利用他在基质免疫串扰方面的专业知识， 系统的方法来理解胸腺稳态和幼稚T细胞的发展跨越生命。 这项研究计划的重点是胸腺上皮细胞在表达一种令人惊讶的作用， 造血限制性细胞因子来建立、维持和支持骨髓基质环境。 我们的初步数据显示，胸腺上皮细胞作为一个意想不到的来源IL-13。使用小鼠模型， 其中IL-13是选择性地删除胸腺上皮，我们提出的目的是剖析其对上皮细胞的影响， 和间充质，骨髓细胞，并间接，幼稚T细胞的特点，从而建立了一个框架， 了解骨髓环境的变化如何塑造幼稚T细胞的特征。 博士米勒提出了一个5年的职业发展计划，在此期间，他将有直接的导师， 博士马克安德森和他的顾问委员会，其中包括一个精心策划的科学领袖小组 在T细胞生物学、2型细胞因子和衰老生物学方面具有专长。他提出的课程，会议 参加研讨会将使他获得新的技术专长，并扩大他的知识基础 以及衰老生物学领域的科学网络。这段时间的训练将在加州大学旧金山分校，这是一个 基础免疫学和科学事业发展的无与伦比的制度环境。此外，本发明还提供了一种方法， 靠近巴克老龄化研究所，并聘请巴克首席执行官埃里克·维丁（Eric Verdin）担任导师 将确保米勒博士的科学和专业成长的老化生物学社区。 在这个职业发展奖完成后，米勒博士将培养技术技能， 领域特定的专业知识，推出一个独立的研究计划，在胸腺稳态和老化。

PROGRAM SUMMARY/ABSTRACT Poor T cell mediated immunity in the elderly is associated with increased morbidity and mortality from infectious diseases, suboptimal cancer immunity, and poor responses to vaccination. Waning T cell immunity is due in part to changes in thymic function beginning in the first decade of life and progressing to thymic involution in early to middle adulthood. However, how stromal-immune crosstalk maintains a differentiated, organized, and functional thymic stromal environment during early life, changes during thymic aging, and modifies naïve T cell character is poorly understood. Dr. Corey Miller’s career focus is to understand the mechanisms underlying medullary thymic function and dysfunction, including during aging, and how these states shape naïve T cell development, with the goal of informing novel immunorestorative therapies. His interest in stromal-immune crosstalk started during his doctoral research as an MD/PhD trainee, where he investigated peripheral sources of the T cell survival cytokine, IL-7. After completing medical school, he chose to forgo residency in favor of postdoctoral training and has focused on epithelial heterogeneity within the thymic medulla, leading to a first author publication in Nature. Dr. Miller’s pursuit of further career development training is based on his desire to leverage his expertise in stromal-immune crosstalk to transition towards a systems approach to understanding thymic homeostasis and naïve T cell development across life. This research proposal focuses on a surprising role for the thymic epithelium in expressing a hematopoietically-restricted cytokine to establish, polarize, and support the medullary stromal environment. Our preliminary data reveal the thymic epithelium as an unexpected source of IL-13. Using a mouse model in which IL-13 is selectively deleted from thymic epithelium, we propose aims to dissect its effects on epithelium and mesenchyme, myeloid cells, and, indirectly, naïve T cell character—thereby establishing a framework for understanding how changes in the medullary environment shape naïve T cell character. Dr. Miller has proposed a 5-year career development plan during which he will have direct mentorship by Dr. Mark Anderson and his advisory committee, which includes a carefully curated group of scientific leaders with expertise in T cell biology, type 2 cytokines, and aging biology. His proposed coursework, conference attendance and workshops will enable him to achieve new technical expertise and expand his knowledge base and scientific network in the field of aging biology. This training period will be spent at UCSF, which is an unrivaled institutional environment for basic immunology and scientific career development. In addition, proximity to the Buck Institute for Research on Aging and engagement of Buck CEO, Eric Verdin, as a mentor will ensure Dr. Miller’s scientific and professional growth within the aging biology community. At the completion of this career development award, Dr. Miller will have cultivated the technical skills and domain-specific expertise to launch an independent research program in thymic homeostasis and aging.