The Role of Lipid Droplets and Associated Proteins in γδT17 Cells Under Psoriatic Conditions
Principal Investigator: Yu-San Kao, Ph.D.
Institution: The Trustees of Princeton University
Grant Mechanism: Early Career Research Grant
Funding Amount: $50,000
Project Start Date: August 1, 2025
Project End Date: July 31, 2026
Status: Active
Keywords:
Project Summary:
Current psoriasis treatments include topical therapies, phototherapy, systemic immune-modulating agents, and biologics, which focus on alleviating symptoms and improving quality of life. While biologics (e.g., neutralizing IL-23 and IL-17) can significantly relieve the symptoms, the disease relapses easily once the patient discontinues the therapy. Further challenges remain, including treatment resistance, adverse effects, high costs, healthcare burden, and variability in individual responses; therefore, a deeper understanding of the pathogenesis of psoriasis is of great interest. The immune system protects our body by eliminating infections by recognizing non-self-antigens on pathogens. Psoriasis is triggered by overactive immune cells attacking the patient’s body without an infection. Scientists identified that the leading cause of psoriasis is driven by specialized immune cells, type 17 T cells. Among type 17 T cells, γδT17 cells amplify the inflammation by responding to psoriatic inflammation without recognizing auto-antigens from the patient’s body. Therefore, understanding how psoriatic inflammation turns these γδT17 pathogenic cells can help us to control or cure the disease. This project aims to elucidate how to target pathogenic γδT17 to provide more insights into psoriasis therapy.
How will your project help improve the lives of the 125 million affected by psoriatic disease?
Current psoriasis treatments include topical therapies, phototherapy, systemic immune modulators, and biologics, focusing on alleviating symptoms and improving quality of life. While biologics (e.g., neutralizing IL-23 and IL-17) can significantly relieve the symptoms, the disease relapses easily once the patient discontinues the therapy. Further challenges remain, including treatment resistance, adverse effects, high costs, healthcare burden, and variability in individual responses; therefore, a deeper understanding of the pathogenesis of psoriasis is of great interest. Psoriasis is associated with comorbidities, such as metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), and dyslipidemia. However, the potential pathogenic role of metabolic dysregulation in the etiology of psoriasis remains poorly understood. In our project, we aim to elucidate the underlying mechanism by which immune cells contribute to the pathogenic source of IL-17, which could provide a new therapeutic option to modulate these pathogenic cells. For instance, our data will uncover the critical metabolic pathway associated with lipid droplet accumulation in one of the leading IL-17 producers, γδT17 cells. Our innovative microenvironment mapping methods, coupled with functional tests, will reveal the role of lipid droplets, thereby providing novel targets. Our study could lead to new therapeutic strategies that more fundamentally address the dysregulation of IL-17 production, potentially achieving more durable remission and improved psoriasis management for patients with psoriatic diseases.
Why is psoriatic disease research important to you, personally? What role will this award play in your research efforts or career development?
I have been working on the metabolic regulation of immune cells involved in psoriatic inflammation since 2019, supported by a fully funded PhD scholarship in Germany. My project was supported by a Collaborative Research Centre (CRC) focusing on skin diseases, funded by the Deutsche Forschungsgemeinschaft (DFG). As an immunologist trained by this program, I had numerous opportunities to collaborate with dermatologists who treat patients with psoriasis daily and understand the remaining challenges in clinical practice. Motivated by the unmet medical demand, I aim to investigate the underlying mechanisms that drive psoriatic inflammation. My studies demonstrated how cell-intrinsic metabolic pathways determine the status of immune systems and found that dysregulated lipid metabolism exacerbates psoriasis inflammation. Meanwhile, psoriatic inflammation triggers the accumulation of lipid droplets in one of the primary IL-17-producing cells, γδT17 cells. However, the role of lipid droplets in γδT17 cells remains uninvestigated. With the support of the National Psoriasis Foundation (NPF), I will investigate whether the accumulation and secretion of lipid droplets in γδT17 cells contribute to the promotion of inflammation in psoriasis. Receiving this award will enable us to investigate the novel functions of lipid droplets in γδT17 cells through a collaborative network with my mentor, Prof. Lydia Lynch, at Princeton University. Furthermore, the results generated from this project will point to the future direction of psoriasis therapy. The award provided by NPF can support me in leading the project, which could lay the foundation for my early career, pave the way for pursuing larger federal or national research grants to establish my research group in the future
Researcher Profile:
Yu-San Kao is a postdoctoral research fellow in Prof. Lydia Lynch's group at Princeton University. She obtained her Ph.D. at the Mainz Research School of Translational Biomedicine (Transmed) and the international PhD program (IPP) of the IMB in the Medical Center of Johannes Gutenberg University in Germany. Her research focuses on the metabolic regulation of T cells in autoimmune skin diseases. Kao’s work demonstrated that targeting Acetyl-CoA carboxylase 1 (ACC1), a rate-limiting enzyme of fatty acid synthesis in T cells, including CD4+, CD8+, and IL-17-producing gamma delta T cells (γδT17 cells), by genetic ablation in mouse models ameliorated psoriatic inflammation. She further employed a combination of high-throughput techniques, including RNA sequencing, SCENITH, proteomics, and stable isotope tracing, to gain insights into how psoriatic inflammation influences the metabolic profile of γδT17 cells. She is investigating novel lipid droplet functions in γδT17 cells by innovative microenvironment mapping methods to provide therapeutic strategies against psoriatic inflammation.