Notch-RBP-J signaling controls the homeostasis of CD8- dendritic cells in the spleen.
Signaling through Notch receptors and their transcriptional effector RBP-J is essential for lymphocyte development and function, whereas its role in other immune cell types is unclear. We tested the function of the canonical Notch-RBP-J pathway in dendritic cell (DC) development and maintenance in vivo. Genetic inactivation of RBP-J in the bone marrow did not preclude DC lineage commitment but caused the reduction of splenic DC fraction. The inactivation of RBP-J in DCs using a novel DC-specific deleter strain caused selective loss of the splenic CD8(-) DC subset and reduced the frequency of cytokine-secreting CD8(-) DCs after challenge with Toll-like receptor ligands. In contrast, other splenic DC subsets and DCs in the lymph nodes and tissues were unaffected. The RBP-J-deficient splenic CD8(-) DCs were depleted at the postprogenitor stage, exhibited increased apoptosis, and lost the expression of the Notch target gene Deltex1. In the spleen, CD8(-) DCs were found adjacent to cells expressing the Notch ligand Delta-like 1 in the marginal zone (MZ). Thus, canonical Notch-RBP-J signaling controls the maintenance of CD8(-) DCs in the splenic MZ, revealing an unexpected role of the Notch pathway in the innate immune system.
Caton
Michele L
ML
Department of Microbiology, Columbia University Medical Center, New York, NY 10032, USA.
Smith-Raska
Matthew R
MR
Reizis
Boris
B
D000818:Animals; D039521:CD11c Antigen / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D005434:Flow Cytometry; D006706:Homeostasis; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019426:Integrases / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D051880:Receptors, Notch / Q000502:physiology; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology*; D051193:Toll-Like Receptors / Q000502:physiology
D039521:CD11c Antigen; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D008070:Lipopolysaccharides; D051880:Receptors, Notch; D051193:Toll-Like Receptors; C045073:Cre recombinase; D019426:Integrases