title: The Src-like adaptor protein regulates GM-CSFR signaling and monocytic dendritic cell maturation.
abstract: GM-CSF is an important cytokine involved in myeloid differentiation and inflammatory processes. Signaling through the GM-CSFR also plays a critical role in the generation of monocyte-derived dendritic cells (DC). In this article, we report that the Src-like adaptor protein (SLAP) functions as a negative regulator of the GM-CSFR. In bone marrow-derived DC (BM-DC) lacking SLAP and the closely related SLAP2, downregulation of GM-CSFRβ is impaired, leading to enhanced phosphorylation of Jak2 and prolonged activation of Akt and Erk1/2 in response to GM-CSF stimulation. Compared with wild-type bone marrow, SLAP/SLAP2(-/-) bone marrow gave rise to similar numbers of CD11c(+) and CD11b(+) DC, but SLAP/SLAP2(-/-) BM-DC failed to acquire high levels of MHC class II, CD80, and CD86, indicating an impairment in maturation. Furthermore, MHC class II expression in SLAP/SLAP2(-/-) BM-DC was rescued by decreasing GM-CSF concentration, suggesting that enhanced GM-CSF signaling mediates the block in maturation. In addition, SLAP/SLAP2(-/-) BM-DC produced less IL-12 and TNF-α in response to LPS compared with controls and failed to stimulate T cells in an MLR. Ag-specific T cell activation assays showed that SLAP/SLAP2(-/-) BM-DC were less robust at inducing IFN-γ secretion by DO11.10 T cells. These results indicated that SLAP-mediated GM-CSFR regulation is important for the generation of functionally mature monocytic DC.
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Larissa M
authors.initials: LM
authors.lastname: Liontos
authors.forename: Dilan
authors.initials: D
authors.lastname: Dissanayake
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
authors.forename: Arthur
authors.initials: A
authors.lastname: Weiss
authors.forename: Leonard L
authors.initials: LL
authors.lastname: Dragone
authors.forename: C Jane
authors.initials: CJ
authors.lastname: McGlade
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D053648:Cytokine Receptor Common beta Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D006131:Growth Inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053648:Cytokine Receptor Common beta Subunit; D006131:Growth Inhibitors; C095148:Sla protein, mouse; C486695:Sla2 protein, mouse; C072186:Csf2rb protein, mouse; D016392:Proto-Oncogene Proteins pp60(c-src)