Project Abstract Research: Asymmetric cell division is an evolutionarily conserved mechanism that affords self-renewal, differentiation and diversification of cell populations. It is unknown, however, if human T cells use this mechanism to induce distinct daughter cell fates. The proposed research will test the hypothesis that asymmetric cell division is an indispensable mechanism of human T cells to generate functionally distinct daughter cells. The experiments will use a novel method of target-induced labeling of the immunological synapse, multicolor flow cytometry, single cell RNA sequencing and metabolomic profiling to identify and ultimately modulate cellular programs that support long- and short-lived progeny induction in both native and genetically-engineered human T cells. A better understanding of cell division patterns will expand our knowledge on human T cell differentiation, uncover factors promoting niche-specific T cell persistence, and establish biology-driven principles and methods for optimization of T cell immunotherapy. Candidate: Dr. Ellebrecht earned his MD from the University of Lubeck, Germany and will complete Dermatology residency training at the University of Pennsylvania in 2021. Dr. Ellebrecht is pursuing postdoctoral training in Dr. Aimee Payne’s and Dr. Carl June’s laboratories at Penn. The 5-year career development plan includes structured coursework and training in single cell transcriptional profiling, bioinformatics, and metabolic profiling of human T cells from experienced mentors and collaborators, along with professional career development activities, with the goal of establishing an independent, NIH-funded research laboratory investigating fate induction and longevity of skin-resident and engineered T cells. Environment: The mentors, Dr. Aimee Payne and Dr. Carl June, are renowned NIH-funded Penn investigators, who provide unparalleled expertise in T cell biology, immunotherapy, metabolomics and single cell characterization of human T cells in combination with an exceptional mentoring record including prior K08 and K23 awardees. Dr. Ellebrecht’s focus on asymmetric cell division in skin resident T cells provides a clear path to independence that sets him apart from Dr. Payne’s and Dr. June’s focus on translational immunotherapy. Dr. Ellebrecht’s research and training will be supported by the Penn Dermatology Department, Center for Cellular Immunotherapy and CHOP metabolomics core, providing state-of the-art core facilities for flow cytometry, cell sorting, single cell sequencing, metabolomics, human skin xenografts and bioinformatics. Taken together, his mentors, collaborators and access to these top-notch technologies will create an ideal environment for Dr. Ellebrecht to thrive on his path towards becoming an independent physician scientist leading efforts to characterize and modulate T cell populations responsible for chronic inflammatory skin diseases.

Project narrative This proposal seeks to elucidate how human T cells use asymmetric cell division to generate long- and short- lived daughter cells with distinct phenotypes, metabolism and functions. The proposal has broad public health relevance, as the cellular mechanism underlying the development of distinct T cell phenotypes determines the clinical outcome of engineered T cell therapeutics. Similarly, a better mechanistic understanding of persistence of skin-resident T cells has significant implications for inflammatory skin disease pathophysiology and treatment.