Dll4-Notch signaling in Flt3-independent dendritic cell development and autoimmunity in mice

• Published in: The Journal of experimental medicine Vol. 209; no. 5; pp. 1011 - 1028
• Main Authors: Billiard, Fabienne, Lobry, Camille, Darrasse-Jèze, Guillaume, Waite, Janelle, Liu, Xia, Mouquet, Hugo, DaNave, Amanda, Tait, Michelle, Idoyaga, Juliana, Leboeuf, Marylène, Kyratsous, Christos A, Burton, Jacquelynn, Kalter, Julie, Klinakis, Apostolos, Zhang, Wen, Thurston, Gavin, Merad, Miriam, Steinman, Ralph M, Murphy, Andrew J, Yancopoulos, George D, Aifantis, Iannis, Skokos, Dimitris
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 07.05.2012
• Subjects: Adaptor Proteins, Signal Transducing; Amyloid Precursor Protein Secretases - deficiency; Amyloid Precursor Protein Secretases - metabolism; Animals; Antibodies - pharmacology; Blotting, Western; Calcium-Binding Proteins; Cell Differentiation - immunology; Dendritic Cells - immunology; Dendritic Cells - physiology; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - prevention & control; DNA Primers - genetics; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Fluorescent Antibody Technique; fms-Like Tyrosine Kinase 3 - genetics; fms-Like Tyrosine Kinase 3 - metabolism; Genes, MHC Class II - immunology; Intracellular Signaling Peptides and Proteins - immunology; Intracellular Signaling Peptides and Proteins - metabolism; Membrane Glycoproteins - deficiency; Membrane Glycoproteins - metabolism; Membrane Proteins - immunology; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Transgenic; Microscopy, Confocal; Oligonucleotide Array Sequence Analysis; Pancreas - pathology; Polymerase Chain Reaction; Receptors, Notch - metabolism; Signal Transduction - immunology; Signal Transduction - physiology; T-Lymphocyte Subsets - immunology; Thymus Gland - cytology; Thymus Gland - immunology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20111615

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.