Colorado Denver Childrens Hospital

Denver, CO, United States

Colorado Denver Childrens Hospital

Denver, CO, United States
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Liontos L.M.,University of Toronto | Liontos L.M.,Hospital for Sick Children | Dissanayake D.,University of Toronto | Dissanayake D.,Ontario Cancer Institute | And 8 more authors.
Journal of Immunology | Year: 2011

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. Copyright©2011 by The American Association of Immunologists, Inc.

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