Targeting antigens to phosphatidylserine triggers rapid T- and B-cell responses

Hu, Wenbo (2025): Targeting antigens to phosphatidylserine triggers rapid T- and B-cell responses. Dissertation, LMU München: Medizinische Fakultät

Abstract

Phosphatidylserine (PS) is a phospholipid that is abundant in cell membranes. In live cells, PS is asymmetrically restrained to the inner leaflet of membrane. In dying cells, activated platelets and extracellular vesicles (EVs), PS is exposed on the membrane surface and it can be bound by PS-binding proteins, such as Milk fat globule epidermal growth factor 8 (Mfge8). In previous studies, we have established use of fluorescent Mfge8 to label and characterize EVs in vivo. Here in this study, we explored the possibility of using Mfge8 as an antigen carrier to load antigens onto PS+ EVs. PS- targeting antigens were created by conjugating antigens to Mfge8 or the tetramerized PS-binding C1 domains of Mfge8. We found that compared with non-targeting conventional antigens, PS-targeting antigens accumulated in the marginal zone of lymphoid follicles soon after injection. Hours later, they were transferred onto the follicular dendritic cell (FDC) network without the need of previous primary immunization. We measured the antigen-specific immune responses elicited by these PS-targeting antigens and found that germinal center (GC) B cell proliferation and somatic hypermutation were significantly enhanced. As a result, serum antigen specific IgG titers were significantly higher than mice immunized with conventional antigens, and antibody isotype switching was greatly accelerated. PS-targeting antigens also induced increased number of T follicular helper cells (Tfh cells) to support GC reaction, as well as more activated CD8 T cells that eliminated target cells more efficiently. Therefore, targeting antigens to PS promoted both B- and T- cell responses, which make it a promising novel vaccination platform.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 15. April 2025
• 1. Bericht­erstatter:in: Brocker, Thomas