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Mammalian target of rapamycin controls dendritic cell development downstream of Flt3 ligand signaling.

ABSTRACT: 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.

SUBMITTER: Sathaliyawala T 

PROVIDER: S-EPMC2966531 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Mammalian target of rapamycin controls dendritic cell development downstream of Flt3 ligand signaling.

Sathaliyawala Taheri T   O'Gorman William E WE   Greter Melanie M   Bogunovic Milena M   Konjufca Vjollca V   Hou Z Esther ZE   Nolan Garry P GP   Miller Mark J MJ   Merad Miriam M   Reizis Boris B  

Immunity 20101007 4

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. Co  ...[more]

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