title: Artificial antigen-presenting cells expressing HLA class II molecules as an effective tool for amplifying human specific memory CD4(+) T cells.
abstract: Owing to their multiple immune functions, CD4(+) T cells are of major interest for immunotherapy in chronic viral infections and cancer, as well as for severe autoimmune diseases and transplantation. Therefore, standardized methods allowing rapid generation of a large number of CD4(+) T cells for adoptive immunotherapy are still awaited. We constructed stable artificial antigen-presenting cells (AAPCs) derived from mouse fibroblasts. They were genetically modified to express human leukocyte antigen (HLA)-DR molecules and the human accessory molecules B7.1, Intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-3 (LFA-3). AAPCs expressing HLA-DR1, HLA-DR15 or HLA-DR51 molecules and loaded with peptides derived from influenza hemagglutinin (HA), myelin basic protein (MBP) or factor VIII, respectively, activated specific CD4(+) T-cell clones more effectively than Epstein-Barr virus (EBV)-transformed B cells. We also showed that AAPCs were able to take up and process whole Ag proteins, and present epitopes to specific T cells. In primary cultures, AAPCs loaded with HA peptide allowed generation of specific Th1 lymphocytes from healthy donors as demonstrated by tetramer and intracellular cytokine staining. Although AAPCs were less effective than autologous peripheral blood mononuclear cells (PBMCs) to stimulate CD4(+) T cells in primary culture, AAPCs were more potent to reactivate and expand memory Th1 cells in a strictly Ag-dependent manner. As the availability of autologous APCs is limited, the AAPC system represents a stable and reliable tool to achieve clinically relevant numbers of CD4(+) T cells for adoptive immunotherapy. For fundamental research in immunology, AAPCs are also useful to decipher mechanisms involved in the development of human CD4 T-cell responses.
authors.affiliation: Inserm U919, Serine Proteases and Pathophysiology of the Neurovascular Unit, Caen, France.|Université de Caen Basse-Normandie, UFR Médecine, Caen, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Garnier
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Rouen, France.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Hamieh
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Rouen, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Drouet
authors.affiliation: Inserm U982, Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Rouen, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Leprince
authors.affiliation: Inserm U919, Serine Proteases and Pathophysiology of the Neurovascular Unit, Caen, France.|Université de Caen Basse-Normandie, UFR Médecine, Caen, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Vivien
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Rouen, France.|Department of Genetics, Rouen University Hospital, Rouen, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Frébourg
authors.affiliation: Inserm U919, Serine Proteases and Pathophysiology of the Neurovascular Unit, Caen, France.|Université de Caen Basse-Normandie, UFR Médecine, Caen, France.|CHU Caen, Department of Immunology and Immunopathology, Caen, France.|Etablissement Français du Sang, Normandie, Caen, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Le Mauff
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Rouen, France.|Department of Genetics, Rouen University Hospital, Rouen, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Latouche
authors.affiliation: Inserm U919, Serine Proteases and Pathophysiology of the Neurovascular Unit, Caen, France.|Université de Caen Basse-Normandie, UFR Médecine, Caen, France.|CHU Caen, Department of Immunology and Immunopathology, Caen, France.|Etablissement Français du Sang, Normandie, Caen, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Toutirais
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology*; D058045:Artificial Cells / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D049109:Cell Proliferation; D000939:Epitopes / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D007156:Immunologic Memory; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D041681:NIH 3T3 Cells; D010455:Peptides / Q000378:metabolism; D010641:Phenotype; D014019:Tissue Donors
chemical_list: D000939:Epitopes; D000949:Histocompatibility Antigens Class II; D010455:Peptides