TOR in the immune system

Department of Microbiology and Immunology, Emory University, Atlanta, Georgia, United States
Current opinion in cell biology (Impact Factor: 8.74). 09/2011; 23(6):707-15. DOI: 10.1016/
Source: PubMed

ABSTRACT The target of rapamycin (TOR) is a crucial intracellular regulator of the immune system. Recent studies have suggested that immunosuppression by TOR inhibition may be mediated by modulating differentiation of both effector and regulatory CD4 T cell subsets. However, it was paradoxically shown that inhibiting TOR signaling has immunostimulatory effects on the generation of long-lived memory CD8 T cells. Beneficial effects of TOR inhibition have also been observed with dendritic cells and hematopoietic stem cells. This immune modulation may contribute to lifespan extension seen in mice with mTOR inhibition. Here, we review recent findings on TOR modulation of innate and adaptive immune responses, and discuss potential applications of regulating TOR to provide longer and healthier immunity.

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Available from: Koichi Araki, Jul 30, 2015
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    • "The early secretion of IL-2 is a key event that discriminates productive activation from anergy (Thompson et al., 1989; Linsley et al., 1991; Harding et al., 1992). IL-2 is necessary (DeSilva et al., 1991) and sufficient (Zheng et al., 2007) to avoid anergy in response to TCR engagement through signaling pathways that include PI3K and mTOR (Powell and Delgoffe, 2010; Liou and Smith, 2011), a PI3K-related Ser/Thr kinase that integrates signals from several pathways including TCR signaling and cellular metabolism (Wells, 2009; Powell and Delgoffe, 2010; Araki et al., 2011). Anergy-inducing stimuli may act in part by inducing the degradation of signaling molecules (Heissmeyer et al., 2004), and evidence that the activation versus anergy decision is affected by the abundance of signaling components comes from the involvement in this process of E3 ubiquitin ligases, enzymes that mediate the proteolytic turnover of signaling molecules: Cbl-b, Itch, and GRAIL are up-regulated in T cells under anergizing stimuli and required for anergy induction (Paolino and Penninger, 2010). "
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    ABSTRACT: T cell receptor (TCR) signals can elicit full activation with acquisition of effector functions or a state of anergy. Here, we ask whether microRNAs affect the interpretation of TCR signaling. We find that Dicer-deficient CD4 T cells fail to correctly discriminate between activating and anergy-inducing stimuli and produce IL-2 in the absence of co-stimulation. Excess IL-2 production by Dicer-deficient CD4 T cells was sufficient to override anergy induction in WT T cells and to restore inducible Foxp3 expression in Il2-deficient CD4 T cells. Phosphorylation of Akt on S473 and of S6 ribosomal protein was increased and sustained in Dicer-deficient CD4 T cells, indicating elevated mTOR activity. The mTOR components Mtor and Rictor were posttranscriptionally deregulated, and the microRNAs Let-7 and miR-16 targeted the Mtor and Rictor mRNAs. Remarkably, returning Mtor and Rictor to normal levels by deleting one allele of Mtor and one allele of Rictor was sufficient to reduce Akt S473 phosphorylation and to reduce co-stimulation-independent IL-2 production in Dicer-deficient CD4 T cells. These results show that microRNAs regulate the expression of mTOR components in T cells, and that this regulation is critical for the modulation of mTOR activity. Hence, microRNAs contribute to the discrimination between T cell activation and anergy.
    Journal of Experimental Medicine 10/2014; 211(11). DOI:10.1084/jem.20132059 · 13.91 Impact Factor
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    • "Therefore, rapamycin may enhance the memory CTL programming by suppressing apoptosis and enhancing survival. There were 14 genes upregulated by rapamycin (Table S2), including CD62L (Araki et al. 2011; Li et al. 2011), which is an important marker for central memory CTL and directs the migration of immune cells to secondary lymphoid tissues (Obar and Lefrancois 2010). Another adhesion molecule, CXCL10, was also enhanced by rapamycin. "
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    ABSTRACT: Memory programming of cytotoxic T cells (CTLs) by inflammatory cytokines can be regulated by mammalian target of rapamycin (mTOR). We have shown that inhibition of mTOR during CTL activation leads to the enhancement of memory, but the molecular mechanisms remain largely unknown. Using high-throughput RNA-Seq, we identified genes and functions in mouse CTLs affected by mTOR inhibition through rapamycin. Of the 43,221 identified transcripts, 184 transcripts were differentially expressed after rapamycin treatment, corresponding to 128 annotated genes. Of these genes, 114 were downregulated and only 14 were upregulated. Most importantly, 50 of them are directly related to cell death and survival. In addition, several genes such as CD62L are related to migration. Furthermore, we predicted downregulation of transcriptional regulators based on the total differentially expressed genes, as well as the subset of apoptosis-related genes. Quantitative PCR confirmed the differential expressions detected in RNA-Seq. We conclude that the regulatory function of rapamycin may work through inhibition of multiple genes related to apoptosis and migration, which enhance CTL survival into memory.
    Immunogenetics 08/2014; 66(11). DOI:10.1007/s00251-014-0790-5 · 2.49 Impact Factor
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    • "In Drosophila, the dTOR pathway is activated downstream of insulin receptor signalling where it controls timing of neuronal differentiation in the eye (Bateman and McNeill, 2004). In mammalian systems, a role for mTOR in directing cell differentiation has been described in immune cells (for review, see Araki et al., 2011), myoblasts (Coolican et al., 1997; Sarbassov and Peterson, 1998; Cho et al., 2004) and adipocytes (Cho et al., 2004). Adipocyte differentiation is perhaps one of the best characterized and most relevant differentiation pathways from extracellular signalling to mTOR to gene transcription (Cho et al., 2004). "
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    ABSTRACT: Oligodendrocyte development is controlled by numerous extracellular signals that regulate a series of transcription factors that promote the differentiation of oligodendrocyte progenitor cells to myelinating cells in the central nervous system. A major element of this regulatory system that has only recently been studied is the intracellular signaling from surface receptors to transcription factors to downregulate inhibitors and upregulate inducers of oligodendrocyte differentiation and myelination. The current review focuses on one such pathway: the mammalian target of rapamycin (mTOR) pathway, which integrates signals in many cell systems and induces cell responses including cell proliferation and cell differentiation. This review describes the known functions of mTOR as they relate to oligodendrocyte development, and its recently discovered impact on oligodendrocyte differentiation and myelination. A potential model for its role in oligodendrocyte development is proposed.
    ASN Neuro 02/2013; 5(1). DOI:10.1042/AN20120092 · 4.44 Impact Factor
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