Derdak, Sophia V.Kueng, Hans J.Leb, Victoria M.Neunkirchner, AlinaSchmetterer, Klaus G.Bielek, EdithMajdic, OttoKnapp, WalterSeed, BrianPickl, Winfried F.2019-10-172006Derdak, S. V., H. J. Kueng, V. M. Leb, A. Neunkirchner, K. G. Schmetterer, E. Bielek, O. Majdic, W. Knapp, B. Seed, and W. F. Pickl. 2006. “Direct Stimulation of T Lymphocytes by Immunosomes: Virus-like Particles Decorated with T Cell Receptor/CD3 Ligands plus Costimulatory Molecules.” Proceedings of the National Academy of Sciences 103 (35). Proceedings of the National Academy of Sciences: 13144–49. doi:10.1073/pnas.0602283103.0027-84240744-28311091-6490http://nrs.harvard.edu/urn-3:HUL.InstRepos:41555779Many infectious viruses coevolved with the vertebrate immune system. During the assembly of enveloped viruses, lipid ordered domains of the host cell plasma membrane, called lipid rafts, frequently function as a natural meeting point for viral proteins. The role of lipid rafts in the organization of complex combinations of immune receptors during antigen presentation and T cell signaling is widely recognized. In our studies, we determined whether lipid rafts, virus budding, and molecular interactions during T cell activation could be brought into a novel context to create artificial antigen-presenting particles. We show here that cell-free virus-like particles (VLP) expressing a surrogate TCR/CD3 ligand (OKT3scFv) and the costimulator CD80 polyclonally activate human T cells independently of accessory cells. VLP expressing the glycoprotein epitope 33-41 of the lymphocytic choriomeningitis virus in the context of H-2D(b) activate and expand naive, antigen-specific CD8(+) T lymphocytes and differentiate them into cytotoxic effector cells. Efficient targeting of T cell ligands to lipid rafts and ultimately to VLP is achieved by C-terminal introduction of glycosyl phosphatidyl inositol acceptor sequences, replacing transmembrane and intracellular domains. In this work, basic functions of immunostimulatory molecules meet virus biology and translate into a reductionist antigen-specific T lymphocyte-stimulating vehicle, which we refer to as immunosomes. A large variety of agonistic and antagonistic accessory molecules on genuine antigen-presenting cells may complicate the predictable manipulation of T cells as well as the analysis of selected receptor combinations, making immunosomes potentially useful reagents for such purposes in the future.en-USJournal Article2019-10-1710.1073/pnas.0602283103