[PDF][PDF] Mammalian target of rapamycin controls dendritic cell development downstream of Flt3 ligand signaling

T Sathaliyawala, WE O'Gorman, M Greter, M Bogunovic… - Immunity, 2010 - cell.com
T Sathaliyawala, WE O'Gorman, M Greter, M Bogunovic, V Konjufca, ZE Hou, GP Nolan
Immunity, 2010cell.com
Dendritic cells (DCs) comprise distinct functional subsets including CD8− and CD8+
classical DCs (cDCs) and interferon-secreting plasmacytoid DCs (pDCs). The cytokine Flt3
ligand (Flt3L) controls the development of DCs and is particularly important for the pDC and
CD8+ cDC and their CD103+ tissue counterparts. We report that mammalian target of
rapamycin (mTOR) inhibitor rapamycin impaired Flt3L-driven DC development in vitro, with
the pDCs and CD8+-like cDCs most profoundly affected. Conversely, deletion of the …
Summary
Dendritic cells (DCs) comprise distinct functional subsets including CD8 and CD8+ classical DCs (cDCs) and interferon-secreting plasmacytoid DCs (pDCs). The cytokine Flt3 ligand (Flt3L) controls the development of DCs and is particularly important for the pDC and CD8+ cDC and their CD103+ tissue counterparts. We report that mammalian target of rapamycin (mTOR) inhibitor rapamycin impaired Flt3L-driven DC development in vitro, with the pDCs and CD8+-like cDCs most profoundly affected. Conversely, deletion of the phosphoinositide 3-kinase (PI3K)-mTOR negative regulator Pten facilitated Flt3L-driven DC development in culture. DC-specific Pten targeting in vivo caused the expansion of CD8+ and CD103+ cDC numbers, which was reversible by rapamycin. The increased CD8+ cDC numbers caused by Pten deletion correlated with increased susceptibility to the intracellular pathogen Listeria. Thus, PI3K-mTOR signaling downstream of Flt3L controls DC development, and its restriction by Pten ensures optimal DC pool size and subset composition.
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