Dissecting mechanisms of trogocytosis and their role in regulating T cell responses
Final Report Abstract
T cells play a crucial role in protecting the body from infections and cancer. Understanding their response is important for developing treatments for various diseases. Most research focuses on how the production of certain proteins helps T cells either become activated or shut down. Our research project, however, investigated how T cells can influence the availability of these proteins not just by producing them, but also by acquiring them from neighboring cells in a process called "trogocytosis." We focused on two proteins - CD28 and CTLA4 - which control T cell behavior by stimulating or inhibiting other T cells, respectively. We discovered that both receptors acquire their shared ligands, CD80 and CD86, from neighboring cells but process them differently. Trogocytosis via CD28 leads to the reuse of these proteins, while CTLA4 sends them to be broken down. This difference is important because it determines how T cells interact with each other as a population during immune responses, specifically whether T cells can mutually boost or inhibit each other’s activity. For example, early in an immune response, when there are fewer T cells, trogocytosis via CD28 helps T cells stimulate each other. But as more T cells accumulate during an immune response, CTLA4-mediated trogocytosis starts to take over, making the mutual interaction between T cells more inhibitory and helping to prevent overshooting and potentially dangerous immune responses. This process and the underlying mechanisms we dissected in this project help to understand how the activity of the immune system is controlled at the T cell population level and could open new ways to modulate T cell behavior for treatments. The study shows that the process of trogocytosis affects how proteins are used by the cell, adding an extra layer of control over how cells communicate and mutually control each other in the immune system.
Publications
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Differential trafficking of ligands trogocytosed via CD28 versus CTLA4 promotes collective cellular control of co-stimulation. Nature Communications, 13(1).
Zenke, Simon; Sica, Mauricio P.; Steinberg, Florian; Braun, Julia; Zink, Alicia; Gavrilov, Alina; Hilger, Alexander; Arra, Aditya; Brunner-Weinzierl, Monika; Elling, Roland; Beyersdorf, Niklas; Lämmermann, Tim; Smulski, Cristian R. & Rohr, Jan C.
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Analyzing trogocytosis of T lymphocytes by flow cytometry and confocal microscopy. STAR Protocols, 4(1), 102013.
Zink, Alicia; Zenke, Simon; Wiese, Teresa; Beyersdorf, Niklas; Lämmermann, Tim & Rohr, Jan C.
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Functional Relevance of CTLA4 Variants: an Upgraded Approach to Assess CTLA4-Dependent Transendocytosis by Flow Cytometry. Journal of Clinical Immunology, 43(8), 2076-2089.
Rojas-Restrepo, Jessica; Sindram, Elena; Zenke, Simon; Haberstroh, Hanna; Mitsuiki, Noriko; Gabrysch, Annemarie; Huebscher, Katrin; Posadas-Cantera, Sara; Krausz, Máté; Kobbe, Robin; Rohr, Jan C.; Grimbacher, Bodo & Gámez-Díaz, Laura
