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

Taheri Sathaliyawala, William E. O'Gorman, Melanie Greter, Milena Bogunovic, Vjollca Konjufca, Z. Esther Hou, Garry P. Nolan, Mark J. Miller, Miriam Merad, Boris Reizis

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98 Scopus citations

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.

Original languageEnglish
Pages (from-to)597-606
Number of pages10
JournalImmunity
Volume33
Issue number4
DOIs
StatePublished - Oct 29 2010

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    Sathaliyawala, T., O'Gorman, W. E., Greter, M., Bogunovic, M., Konjufca, V., Hou, Z. E., Nolan, G. P., Miller, M. J., Merad, M., & Reizis, B. (2010). Mammalian target of rapamycin controls dendritic cell development downstream of Flt3 ligand signaling. Immunity, 33(4), 597-606. https://doi.org/10.1016/j.immuni.2010.09.012