title: A novel Flt3-deficient HIS mouse model with selective enhancement of human DC development.
abstract: Humanized mice harboring human immune systems (HIS) represent a platform to study immune responses against pathogens and to screen vaccine candidates and novel immunotherapeutics. Innate and adaptive immune responses are suboptimal in HIS mice, possibly due to poor reconstitution of human antigen-presenting cells, including dendritic cells (DCs). DC homeostasis is regulated by cytokine availability, and Flt3-ligand (Flt3L) is one factor that conditions this process. Mouse myelopoiesis is essentially normal in most current HIS models. As such, developing mouse myeloid cells may limit human DC reconstitution by reducing available Flt3L and by cellular competition for specific "niches." To address these issues, we created a novel HIS model that compromises host myeloid cell development via deficiency in the receptor tyrosine kinase Flk2/Flt3. In Balb/c Rag2(-/-) Il2rg(-/-) Flt3(-/-) (BRGF) recipients, human conventional DCs and plasmacytoid DCs develop from hCD34(+) precursors and can be specifically boosted with exogenous Flt3L. Human DCs that develop in this context normally respond to TLR stimulation, and improved human DC homeostasis is associated with increased numbers of human NK and T cells. This new HIS-DC model should provide a means to dissect human DC differentiation and represents a novel platform to screen immune adjuvants and DC targeting therapies.
authors: Innate Immunity Unit, Immunology Department, Institut Pasteur, Paris, France.|Inserm U1223, Institut Pasteur, Paris, France.
authors: Yan
authors: Y
authors: Li
authors: Innate Immunity Unit, Immunology Department, Institut Pasteur, Paris, France.|Inserm U1223, Institut Pasteur, Paris, France.
authors: Jean-Jacques
authors: JJ
authors: Mention
authors: Innate Immunity Unit, Immunology Department, Institut Pasteur, Paris, France.|Inserm U1223, Institut Pasteur, Paris, France.
authors: Nathalie
authors: N
authors: Court
authors: Innate Immunity Unit, Immunology Department, Institut Pasteur, Paris, France.|Inserm U1223, Institut Pasteur, Paris, France.
authors: Guillemette
authors: G
authors: Masse-Ranson
authors: Inserm U1160, Hôpital Saint Louis, Paris, France.
authors: Antoine
authors: A
authors: Toubert
authors: Department of Cell Biology and Histology, Academic Medical Center of the University of Amsterdam (AMC-UvA), Center for Immunology Amsterdam (CIA), Amsterdam, The Netherlands.|Tytgat Institute for Liver and Intestinal Research, Academic Medical Center of the University of Amsterdam (AMC-UvA), Amsterdam, The Netherlands.
authors: Hergen
authors: H
authors: Spits
authors: AXENIS, Paris, France.
authors: Nicolas
authors: N
authors: Legrand
authors: AXENIS, Paris, France.
authors: Erwan
authors: E
authors: Corcuff
authors: Innate Immunity Unit, Immunology Department, Institut Pasteur, Paris, France.|Inserm U1223, Institut Pasteur, Paris, France.
authors: Helene
authors: H
authors: Strick-Marchand
authors: Innate Immunity Unit, Immunology Department, Institut Pasteur, Paris, France.|Inserm U1223, Institut Pasteur, Paris, France.
authors: James P
authors: JP
authors: Di Santo
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000276:immunology* / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000502:physiology; D055611:Natural Killer T-Cells / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology; D051941:fms-Like Tyrosine Kinase 3 / Q000172:deficiency* / Q000235:genetics
chemical_list: D000276:Adjuvants, Immunologic; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3
keywords: Adjuvants; Cytokines; Dendritic cells; Humanized mice; Innate immunity