mk-2206 and Immunologic-Deficiency-Syndromes

Development of dendritic cells (DCs) commences in the bone marrow, from where pre-DCs migrate to peripheral organs to differentiate into mature DCs in situ. However, the factors that regulate organ-specific differentiation to give rise to tissue-specific DC subsets remain unclear. Here we show that the Ras-PI3Kγ-Akt-mTOR signaling axis acted downstream of FLT3L signaling and was required for development of lung CD103(+) DCs and, to a smaller extent, for lung CD11b(+) DCs, but not related DC populations in other non-lymphoid organs. Furthermore, we show that in lymphoid organs such as the spleen, DCs depended on a similar signaling network to respond to FLT3 ligand with overlapping and partially redundant roles for kinases PI3Kγ and PI3Kδ. Thus we identified PI3Kγ as an essential organ-specific regulator of lung DC development and discovered a signaling network regulating tissue-specific DC development mediated by FLT3.

Topics: Animals; Apoptosis; Cell Differentiation; Class Ib Phosphatidylinositol 3-Kinase; Dendritic Cells; fms-Like Tyrosine Kinase 3; Heterocyclic Compounds, 3-Ring; Homeostasis; Immunologic Deficiency Syndromes; Lung; Lymphoid Tissue; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Multiprotein Complexes; Organ Specificity; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins p21(ras); Radiation Chimera; Recombinant Proteins; Signal Transduction; TOR Serine-Threonine Kinases