title: Dll4-Notch signaling in Flt3-independent dendritic cell development and autoimmunity in mice.
abstract: Delta-like ligand 4 (Dll4)-Notch signaling is essential for T cell development and alternative thymic lineage decisions. How Dll4-Notch signaling affects pro-T cell fate and thymic dendritic cell (tDC) development is unknown. We found that Dll4 pharmacological blockade induces accumulation of tDCs and CD4(+)CD25(+)FoxP3(+) regulatory T cells (T(reg) cells) in the thymic cortex. Both genetic inactivation models and anti-Dll4 antibody (Ab) treatment promote de novo natural T(reg) cell expansion by a DC-dependent mechanism that requires major histocompatibility complex II expression on DCs. Anti-Dll4 treatment converts CD4(-)CD8(-)c-kit(+)CD44(+)CD25(-) (DN1) T cell progenitors to immature DCs that induce ex vivo differentiation of naive CD4(+) T cells into T(reg) cells. Induction of these tolerogenic DN1-derived tDCs and the ensuing expansion of T(reg) cells are Fms-like tyrosine kinase 3 (Flt3) independent, occur in the context of transcriptional up-regulation of PU.1, Irf-4, Irf-8, and CSF-1, genes critical for DC differentiation, and are abrogated in thymectomized mice. Anti-Dll4 treatment fully prevents type 1 diabetes (T1D) via a T(reg) cell-mediated mechanism and inhibits CD8(+) T cell pancreatic islet infiltration. Furthermore, a single injection of anti-Dll4 Ab reverses established T1D. Disease remission and recurrence are correlated with increased T(reg) cell numbers in the pancreas-draining lymph nodes. These results identify Dll4-Notch as a novel Flt3-alternative pathway important for regulating tDC-mediated T(reg) cell homeostasis and autoimmunity.
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Billiard
authors.forename: Camille
authors.initials: C
authors.lastname: Lobry
authors.forename: Guillaume
authors.initials: G
authors.lastname: Darrasse-Jèze
authors.forename: Janelle
authors.initials: J
authors.lastname: Waite
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.forename: Hugo
authors.initials: H
authors.lastname: Mouquet
authors.forename: Amanda
authors.initials: A
authors.lastname: DaNave
authors.forename: Michelle
authors.initials: M
authors.lastname: Tait
authors.forename: Juliana
authors.initials: J
authors.lastname: Idoyaga
authors.forename: Marylène
authors.initials: M
authors.lastname: Leboeuf
authors.forename: Christos A
authors.initials: CA
authors.lastname: Kyratsous
authors.forename: Jacquelynn
authors.initials: J
authors.lastname: Burton
authors.forename: Julie
authors.initials: J
authors.lastname: Kalter
authors.forename: Apostolos
authors.initials: A
authors.lastname: Klinakis
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.forename: Gavin
authors.initials: G
authors.lastname: Thurston
authors.forename: Miriam
authors.initials: M
authors.lastname: Merad
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Steinman
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
authors.forename: Dimitris
authors.initials: D
authors.lastname: Skokos
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015153:Blotting, Western; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation / Q000276:immunology*; D017931:DNA Primers / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology / Q000502:physiology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005802:Genes, MHC Class II / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D020411:Oligonucleotide Array Sequence Analysis; D010179:Pancreas / Q000473:pathology; D016133:Polymerase Chain Reaction; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D051880:Receptors, Notch; C413604:nicastrin protein; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3; D053829:Amyloid Precursor Protein Secretases