Mammalian Target of Rapamycin Integrates Diverse Inputs To Guide the Outcome of Antigen Recognition in T Cells

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
The Journal of Immunology (Impact Factor: 4.92). 05/2012; 188(10):4721-9. DOI: 10.4049/jimmunol.1103143
Source: PubMed


T cells must integrate a diverse array of intrinsic and extrinsic signals upon Ag recognition. Although these signals have canonically been categorized into three distinct events--Signal 1 (TCR engagement), Signal 2 (costimulation or inhibition), and Signal 3 (cytokine exposure)--it is now appreciated that many other environmental cues also dictate the outcome of T cell activation. These include nutrient availability, the presence of growth factors and stress signals, as well as chemokine exposure. Although all of these distinct inputs initiate unique signaling cascades, they also modulate the activity of the evolutionarily conserved serine/threonine kinase mammalian target of rapamycin (mTOR). Indeed, mTOR serves to integrate these diverse environmental inputs, ultimately transmitting a signaling program that determines the fate of newly activated T cells. In this review, we highlight how diverse signals from the immune microenvironment can guide the outcome of TCR activation through the activation of the mTOR pathway.

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Available from: Adam T Waickman, Jun 17, 2014
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    • "We have previously demonstrated that rapamycin, an immunomodulatory agent, can induce operational tolerance in patients with sickle cell disease following non myloablative bone marrow transplant resulting in stable mixed chimerism, even in the absence of long-term immunosuppression [5] Rapamycin blocks the mTOR kinase which integrates multiple signals from the TCR (signal 1) as well as signals generated by costimulatory receptors (signal 2). Signal 1 activation of naïve CD4 cells in the presence of mTOR inhibition by rapamycin renders the cells regulatory T cells [6], [7]. While Valle et al have tested the combination of anti CD3 and Rapamycin in the hyperglycemic NOD mice and concluded that rapamycin breaks anti CD3 induced tolerance [8], their data is more consistent with temporary reversible beta cell toxicity from rapamycin administration. "
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    ABSTRACT: Non-Fc-binding Anti CD3 antibody has proven successful in reverting diabetes in the non-obese diabetes mouse model of type 1 diabetes and limited efficacy has been observed in human clinical trials. We hypothesized that addition of rapamycin, an mTOR inhibitor capable of inducing operational tolerance in allogeneic bone marrow transplantation, would result in improved diabetes reversal rates and overall glycemia. Seventy hyperglycemic non-obese diabetic mice were randomized to either a single injection of anti CD3 alone or a single injection of anti CD3 followed by 14 days of intra-peritoneal rapamycin. Mice were monitored for hyperglycemia and metabolic control. Mice treated with the combination of anti CD3 and rapamycin had similar rates of diabetes reversal compared to anti CD3 alone (25/35 vs. 22/35). Mice treated with anti CD3 plus rapamycin had a significant improvement in glycemia control as exhibited by lower blood glucose levels in response to an intra-peritoneal glucose challenge; average peak blood glucose levels 30 min post intra-peritoneal injection of 2 gr/kg glucose were 6.9 mmol/L in the anti CD3 plus rapamycin group vs. 10 mmo/L in the anti CD3 alone (P<0.05). The addition of rapamycin to anti CD3 results in significant improvement in glycaemia control in diabetic NOD mice.
    PLoS ONE 06/2013; 8(6):e67189. DOI:10.1371/journal.pone.0067189 · 3.23 Impact Factor
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    • "It is important to remember that other inputs in addition to TCR and CD28-induced PI3K/AKT are able to activate mTOR. In particular, chemokine receptors via p110γ, cellular energy stores by regulating the adenosine monophosphatedependent kinase (AMPK) pathway, cytoplasmic amino acids via the Ras-related small GTPase Rag proteins, and hypoxia via the hypoxia-induced factor protein regulated in the development of DNA damage response 1 (REDD1)/hypoxia-induced factor 1α (HIF1α) pathway, ERK and RSK downstream of Ras, and phosphatidic acid produced by phospholipase D are potent regulators of mTOR activation [reviewed in Laplante and Sabatini (2012); Waickman and Powell (2012)]. The capacity of these inputs to regulate mTOR activation in T cells is reflected by the ability of 2-deoxyglucose (2-DG) mimicking glucose deprivation, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) mimicking cellular energy depletion, and n-acetyl leucine (NALA) mimicking amino acid depletion to result in anergy when present during CD3/CD28 stimulation of T cells, analogous to rapamycin treatment (Zheng et al., 2009). "
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    ABSTRACT: The mechanistic target of rapamycin (mTOR) is emerging as playing a central role in regulating T cell activation, differentiation, and function. mTOR integrates diverse signals from the immune microenvironment to shape the outcome of T cell receptor (TCR) antigen recognition. Phosphatidylinositol 3-kinase (PI3K) enzymes are critical mediators of T cell activation through their generation of the second messenger phosphatidylinositol (3,4,5) triphosphate (PIP3). Indeed, PIP3 generation results in the activation of Protein Kinase B (PKB, also known as AKT), a key activator of mTOR. However, recent genetic studies have demonstrated inconsistencies between PI3K disruption and loss of mTOR expression with regard to the regulation of effector and regulatory T cell homeostasis and function. In this review, we focus on how PI3K activation directs mature CD4 T cell activation and effector function by pathways dependent on and independent of mTOR signaling. Importantly, what has become clear is that targeting both mTOR-dependent and mTOR-independent PI3K-induced signaling distally affords the opportunity for more selective regulation of T cell differentiation and function.
    Frontiers in Immunology 10/2012; 3:312. DOI:10.3389/fimmu.2012.00312
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    • "In addition, the immunosuppressant Rapamycin (Sirolimus, Rapamune © ), targets mTOR, which reduces T cell proliferation (Sigal and Dumont, 1992). However, more recent exciting findings suggest that Rapamycin may be able to manipulate CD8 + T cell responses, enhancing long term development of CD8 + memory T cells, In addition, Rapamycin may be able to alter the development of CD4 + T helper subsets (Th1/2/17/Treg) (Waickman and Powell, 2012, Chi, 2012). More recent efforts have focused on targeted ZAP-70, Itk, PI3K, and MAPK (Hirabayashi et al., 2009, Lo, 2010, Norman, 2011, Chung, 2011, Trujillo, 2011). "
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    ABSTRACT: T cells play an indispensable role in immune defense against infectious agents, but can also be pathogenic. These T cells develop in the thymus, are exported into the periphery as naïve cells and participate in immune responses. Upon recognition of antigen, they are activated and differentiate into effector and memory T cells. While effector T cells carry out the function of the immune response, memory T cells can last up to the life time of the individual, and are activated by subsequent antigenic exposure. Throughout this life cycle, the T cell uses the same receptor for antigen, the T cell Receptor, a complex multi-subunit receptor. Recognition of antigen presented by peptide/MHC complexes on antigen presenting cells unleashes signaling pathways that control T cell activation at each stage. In this review, we discuss the signals regulated by the T cell receptor in naïve and effector/memory T cells.
    The international journal of biochemistry & cell biology 09/2012; 44(12):2129-2134. DOI:10.1016/j.biocel.2012.08.023 · 4.05 Impact Factor
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