Mammalian Target of Rapamycin Controls Dendritic Cell Development Downstream of Flt3 Ligand Signaling

SummaryDendritic 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.

► Flt3L induces mammalian target of rapamycin (mTOR) signaling in dendritic cells (DCs) ► Flt3L-driven DC development is impaired by rapamycin and accelerated by Pten deletion ► DC-specific deletion of Pten causes mTOR-dependent expansion of CD8+ DC numbers ► DC-specific deletion of Pten impairs immunity to Listeria infection