Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
Immunity. 2010 Oct 29;33(4):597-606. doi: 10.1016/j.immuni.2010.09.012. Epub 2010 Oct 7.
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.
树突状细胞 (DCs) 包括不同的功能亚群，包括 CD8⁻ 和 CD8(+) 经典 DCs (cDCs) 和分泌干扰素的浆细胞样 DCs (pDCs)。细胞因子 Flt3 配体 (Flt3L) 控制 DC 的发育，对 pDC 和 CD8(+) cDC 及其 CD103(+) 组织对应物尤为重要。我们报告称，哺乳动物雷帕霉素靶蛋白 (mTOR) 抑制剂雷帕霉素在体外损害了 Flt3L 驱动的 DC 发育，其中 pDC 和 CD8(+)样 cDC 受到的影响最为严重。相反，磷酸肌醇 3-激酶 (PI3K)-mTOR 负调节剂 Pten 的缺失促进了培养中 Flt3L 驱动的 DC 发育。体内 DC 特异性 Pten 靶向导致 CD8(+) 和 CD103(+) cDC 数量增加，雷帕霉素可使其逆转。由 Pten 缺失引起的 CD8(+) cDC 数量增加与对细胞内病原体李斯特菌的易感性增加相关。因此，Flt3L 下游的 PI3K-mTOR 信号控制 DC 的发育，而 Pten 的限制可确保最佳的 DC 池大小和亚群组成。
