title: CD8+ T Cell Fate and Function Influenced by Antigen-Specific Virus-Like Nanoparticles Co-Expressing Membrane Tethered IL-2.
abstract: A variety of adjuvants fostering humoral immunity are known as of today. However, there is a lack of adjuvants or adjuvant strategies, which directly target T cellular effector functions and memory. We here determined whether systemically toxic cytokines such as IL-2 can be restricted to the site of antigen presentation and used as 'natural adjuvants'. Therefore, we devised antigen-presenting virus-like nanoparticles (VNP) co-expressing IL-2 attached to different membrane-anchors and assessed their potency to modulate CD8+ T cell responses in vitro and in vivo. Efficient targeting of IL-2 to lipid rafts and ultimately VNP was achieved by fusing IL-2 at its C-terminus to a minimal glycosylphosphatidylinositol (GPI)-anchor acceptor sequence. To identify optimal membrane-anchor dimensions we inserted one (1Ig), two (2Ig) or four (4Ig) immunoglobulin(Ig)-like domains of CD16b between IL-2 and the minimal GPI-anchor acceptor sequence of CD16b (GPI). We found that the 2IgGPI version was superior to all other evaluated IL-2 variants (IL-2v) in terms of its i) degree of targeting to lipid rafts and to the VNP surface, ii) biological activity, iii) co-stimulation of cognate T cells in the absence of bystander activation and iv) potency to induce differentiation and acquisition of CD8+ T cell effector functions in vitro and in vivo. In contrast, the GPI version rather favored memory precursor cell formation. These results exemplify novel beneficial features of membrane-bound IL-2, which in addition to its mere T cell stimulatory capacity include the induction of differential effector and memory functions in CD8+ T lymphocytes.
authors.affiliation: Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria; Christian Doppler Laboratory for Immunomodulation, Vienna, Austria.
authors.forename: Daniela
authors.initials: D
authors.lastname: Wojta-Stremayr
authors.affiliation: Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria; Christian Doppler Laboratory for Immunomodulation, Vienna, Austria.
authors.forename: Alina
authors.initials: A
authors.lastname: Neunkirchner
authors.affiliation: Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: Bharani
authors.initials: B
authors.lastname: Srinivasan
authors.affiliation: Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: Doris
authors.initials: D
authors.lastname: Trapin
authors.affiliation: Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
authors.forename: Klaus G
authors.initials: KG
authors.lastname: Schmetterer
authors.affiliation: Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria; Christian Doppler Laboratory for Immunomodulation, Vienna, Austria.
authors.forename: Winfried F
authors.initials: WF
authors.lastname: Pickl
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation; D002460:Cell Line; D058851:GPI-Linked Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D007156:Immunologic Memory; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation; D021962:Membrane Microdomains / Q000276:immunology; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008979:Moloney murine leukemia virus / Q000235:genetics / Q000276:immunology; D053758:Nanoparticles; D017434:Protein Structure, Tertiary; D017452:Receptors, IgG / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D058425:Vaccines, Virus-Like Particle / Q000235:genetics / Q000276:immunology*
chemical_list: C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D007376:Interleukin-2; D017452:Receptors, IgG; D058425:Vaccines, Virus-Like Particle