title: Priming of Qualitatively Superior Human Effector CD8+ T Cells Using TLR8 Ligand Combined with FLT3 Ligand.
abstract: The quality of Ag-specific CD8(+) T cell responses is central to immune efficacy in infectious and malignant settings. Inducing effector CD8(+) T cells with potent functional properties is therefore a priority in the field of immunotherapy. However, the optimal assessment of new treatment strategies in humans is limited by currently available testing platforms. In this study, we introduce an original model of in vitro CD8(+) T cell priming, based on an accelerated dendritic cell coculture system, which uses unfractionated human PBMCs as the starting material. This approach enables the rapid evaluation of adjuvant effects on the functional properties of human CD8(+) T cells primed from Ag-specific naive precursors. We demonstrate that a selective TLR8 agonist, in combination with FLT3L, primes high-quality CD8(+) T cell responses. TLR8L/FLT3L-primed CD8(+) T cells displayed enhanced cytotoxic activity, polyfunctionality, and Ag sensitivity. The acquisition of this superior functional profile was associated with increased T-bet expression induced via an IL-12-dependent mechanism. Collectively, these data validate an expedited route to vaccine delivery or optimal T cell expansion for adoptive cell transfer.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, DHU FAST, CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France.|INSERM, U1135, CIMI-Paris, Paris, France.
authors.forename: Anna
authors.initials: A
authors.lastname: Lissina
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, DHU FAST, CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France.|INSERM, U1135, CIMI-Paris, Paris, France.
authors.forename: Olivia
authors.initials: O
authors.lastname: Briceño
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Institut Cochin, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors.forename: Georgia
authors.initials: G
authors.lastname: Afonso
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, DHU FAST, CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France.|INSERM, U1135, CIMI-Paris, Paris, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Larsen
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Institut Cochin, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.|Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Service de Diabétologie, Paris, France.
authors.forename: Roberto
authors.initials: R
authors.lastname: Mallone
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, DHU FAST, CR7, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France.|INSERM, U1135, CIMI-Paris, Paris, France.
authors.forename: Victor
authors.initials: V
authors.lastname: Appay
mesh_terms: D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D053765:Interleukin-12 Subunit p35 / Q000276:immunology; D015847:Interleukin-4 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008565:Membrane Proteins / Q000494:pharmacology*; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000637:transplantation; D051200:Toll-Like Receptor 8 / Q000819:agonists* / Q000276:immunology
chemical_list: C508858:IL12A protein, human; C508598:IL4 protein, human; D053765:Interleukin-12 Subunit p35; D008565:Membrane Proteins; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8; C084881:flt3 ligand protein; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor