A Versatile Role of Mammalian Target of Rapamycin in Human Dendritic Cell Function and Differentiation

Abstract

The mammalian target of rapamycin (mTOR) regulates cell growth and survival and exists as rapamycin-sensitive mTOR complex (mTORC) 1 and as rapamycin-insensitive mTORC2. Although mTOR is a well-known regulator of diverse immune cells, its detailed role in human dendritic cell (DC) function and differentiation is only incompletely understood. In this study, we demonstrate divergent roles of mTOR during activation and differentiation of myeloid DCs (mDCs) and monocyte-derived DCs (moDCs). Inhibition of mTORC1 in mDCs activated with TLR-dependent or -independent stimuli increased proinflammatory cytokines and NF-κB, whereas IL-10 and STAT3 were blocked. Rapamycin regulated the costimulatory/surface molecules CD86, programmed death ligand-1, and CD25 on mDCs and significantly increased the T cell allostimulatory potential of mDCs. In contrast, rapamycin suppressed immunostimulatory molecules and the allostimulatory potential of LPS-stimulated moDCs by an inability to augment NF-κB signaling. In differentiating moDCs, the PI3K/Akt-dependent mTOR pathway was constitutively activated by GM-CSF to induce DC differentiation in an mTORC1-dependent manner. Inhibition of mTORC1 or mTORC1/2 during moDC differentiation decreased moDC survival and markedly hampered its immunostimulatory phenotype. Analyzing the fate of DCs in vivo, we found that kidney transplant patients treated with rapamycin displayed an increased immunostimulatory potential of mDCs compared with patients treated with calcineurin inhibitors. Furthermore, rapamycin did not interfere with mDC differentiation in these patients. Collectively, mTOR exerts divergent immunoregulatory functions during DC activation and differentiation depending on the DC type that lead to opposing T cell responses, which might be of clinical importance in transplantation, cancer, and also for novel vaccination strategies.

TSC1 controls IL-1β expression in macrophages via mTORC1-dependent C/EBPβ pathway

“…In TSC2-deficient MEFs, pro-inflammatory responses are decreased due to impaired IKK activation and NF-kB translation to the nuclei 44 . However, other studies reported that Rapa treatment enhances IL-12 production in myeloid DCs by promoting NF-kB activation but inhibits IL-12 production in monocyte-derived DCs and bone marrow-derived DCs 20,45 .…”

ESX-1 dependent impairment of autophagic flux byMycobacterium tuberculosisin human dendritic cells

“…Previous findings showed that rapamycin suppressed immunostimulatory molecules and the allostimulatory potential of LPS-stimulated DC. 26 However, when we investigated by flow cytometry analysis the immunophenotype of DC, no major differences were observed on the Mtb-induced expression of the molecules involved in T cell activation, such as CD86, CD83, HLA-DR and CD38 (Table 1). Also, no modulation of Mtb-induced tumor necrosis factor (TNF) production was observed upon rapamycin treatment (Fig.…”

“…Given the inhibitory effect exerted by IL4 on autophagy 25 and the activation of MTOR pathway by CSF2 and IL4 along monocyte-derived DC, 26 we compared in preliminary experiments the effect of Mtb infection on the autophagic process in the presence of CSF2 and IL4 or following the replacement of the differentiating medium 20 h before infection. Having found that both the basal and Mtbdriven autophagic response was altered by the presence of IL4 and CSF2 (data not shown), we decided to perform our study in DC starved from these differentiating cytokines.…”

Dendritic cells from human mesenteric lymph nodes in inflammatory and non‐inflammatory bowel diseases: subsets and function of plasmacytoid dendritic cells

“…8 Mucosal pDC and mDC have been investigated in only a few human studies, although accumulation of activated DC at the sites of inflammation may contribute to the pathogenesis of human inflammatory bowel disease (IBD). 6,[9][10][11][12] Reduced proportions of immature pDC have been found in the peripheral blood (PB) of patients with IBD, suggesting their recruitment to inflamed mucosal tissues. 13,14 Additionally, mesenteric lymph node (MLN) pDC express the chemokine receptor CCR6, which could explain musosal accumulation at inflamed tissue sites as a consequence of up-regulated mucosal addressines such as CCL20 or mucosal addressin cell adhesion molecule-1.…”