Mammalian target of rapamycin controls dendritic cell development downstream of Flt3 ligand signaling
| Autor: | Miriam Merad, Milena Bogunovic, Boris Reizis, William E. O'Gorman, Garry P. Nolan, Taheri Sathaliyawala, Mark J. Miller, Melanie Greter, Z. Esther Hou, Vjollca Konjufca |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
medicine.medical_treatment
Immunology Biology CD8-Positive T-Lymphocytes Protein Serine-Threonine Kinases 03 medical and health sciences Mice Phosphatidylinositol 3-Kinases 0302 clinical medicine Antigens CD medicine PTEN Immunology and Allergy Animals Listeriosis PI3K/AKT/mTOR pathway Cells Cultured 030304 developmental biology Sirolimus 0303 health sciences TOR Serine-Threonine Kinases Intracellular Signaling Peptides and Proteins PTEN Phosphohydrolase Membrane Proteins hemic and immune systems Dendritic cell Dendritic Cells In vitro Mice Inbred C57BL Cytokine Infectious Diseases Cancer research biology.protein Signal transduction Integrin alpha Chains CD8 030215 immunology Signal Transduction |
| Zdroj: | Immunity. 33(4) |
| ISSN: | 1097-4180 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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