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The Src-like adaptor protein regulates GM-CSFR signaling and monocytic dendritic cell maturation.

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.

Pubmed ID: 21220694

Authors

  • Liontos LM
  • Dissanayake D
  • Ohashi PS
  • Weiss A
  • Dragone LL
  • McGlade CJ

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Data

February 15, 2011

Associated Grants

  • Agency: Canadian Institutes of Health Research, Id: MOP12859

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Cell Differentiation
  • Cytokine Receptor Common beta Subunit
  • Dendritic Cells
  • Down-Regulation
  • Growth Inhibitors
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Monocytes
  • Proto-Oncogene Proteins pp60(c-src)
  • Signal Transduction