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

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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.