M. effector, and memory CD4+ or CD8+ T cells, mediate antigen-specific immune responses to pathogens. iNKT cells are a nonconventional T cell population with diverse functions . Dysregulation of conventional and non-conventional T cell responses promotes autoimmune and other immune-mediated disorders [5, 6]. Tregs curtail excessive immune reactions and are classified into 3 groups according to the newest nomenclature: tTregs, pTregs, or iTregs [6, 7]. In this review, we delineate how mTOR signaling functionally regulates metabolism to influence T cell biology, with a particular focus on its impacts on Tregs . RETF-4NA First, we discuss how upstream signaling pathways tune mTOR activation. Next, the role of mTOR in RETF-4NA thymocyte development is discussed. Third, we summarize the roles of mTOR in T cell homeostasis and functional activation. We then describe how mTOR and metabolic signaling cooperate to influence multiple aspects of Treg biology. Finally, we discuss the implications for targeting mTOR or metabolic pathways for disease therapeutics. REGULATION OF mTOR ACTIVITY IN T CELLS mTOR is usually activated by 3 major instructive signals in T cells: immunologic signals, growth factors, and nutrient and metabolic cues . Below, we discuss the molecular events driving mTOR activation downstream of various receptor systems. Overview of canonical signal transduction pathways in T RETF-4NA cells TCR stimulation is critical for the generation of antigen-specific, adaptive immune responses. The TCR recognizes specific antigenic peptides expressed in the context of peptide-MHC molecules that are presented by professional APCs. RETF-4NA TCR signal transduction is initiated by the tyrosine kinases, Lck/Fyn and ZAP70. Subsequently, LAT-containing complexes promote PLC-and Ras-Mek1/2-Erk1/2 activity. These kinase pathways indirectly activate NF-and DGKdouble-deficient T cells have enhanced mTORC1 and Ras-Mek1/2-Erk1/2 signaling . The alteration of the structure of amino acids also inhibits mTORC1 activation. BCATc is activated upon TCR stimulation, which increases Leu transamination and subsequently diminishes the intracellular concentrations of Leu . BCATc-deficient CD4+ T cells have increased phosphorylation of S6 and 4EBP-1 and have higher rates of glycolysis . Thus, BCATc is an inhibitor of mTORC1 downstream of the TCR. Cytokines induce mTOR activation in T cells Cytokines activate mTOR. IL-7 signals via IL-7R to promote T cell development and homeostasis . In contrast with the rapid activation Rabbit Polyclonal to AurB/C of mTOR by the TCR, IL-7 induces delayed and sustained PI3K-AKT signaling, and IL-7-induced mTOR activation is usually STAT5-dependent [27, 28]. IL-15 is usually another homeostatic cytokine that regulates memory T cell RETF-4NA formation [26, 29], but IL-15-driven PI3K-mTOR activation in na?ve T cells is not required for memory T cell formation . IL-2 promotes T cell proliferation, Treg development, and Treg functional activation . IL-2R signaling drives these functions by activating the Jak3-STAT5 and PI3K-Akt-mTORC1 pathways, triggering transcriptional and metabolic reprogramming [1, 26]. Recent studies also link the tyrosine kinase, inducible Tec kinase, to IL-2-induced mTOR activation, but the mechanisms are not completely comprehended . In Tregs, IL-2R signaling augments TCR-induced mTOR activation . Additional cytokines, such as IL-12, IL-4, and IL-1, influence the effector fate decisions of T cells . In activated CD8+ T cells, IL-12 triggers the STAT4-dependent activation of mTOR . IL-4 and IL-1 promote cell-cycle progression by activating mTOR in Th2 and Th17 cells, respectively [35, 36]. We describe how mTOR is usually linked to effector and memory CD4+ and CD8+ differentiation in more detail below. mTOR activity is usually regulated by various growth factors in T cells Many growth factors positively regulate mTOR activation. Leptin, an adipocyte-derived hormone, drives T.
- Next Indeed, cell connection occurs using one side from the cell in 2D cell lifestyle systems, whereas cell connection can be noticed around the complete surface from the cell in 3D cell lifestyle systems (Baker and Chen 2012)
- Previous iNOS-expressing myeloid cells are referred to as classically-activated often, and taken into consideration pro-inflammatory, predicated on their similarity to bone tissue marrow derived macrophages (BMDM) polarized with LPS or IFN by polarization with IL-4 or IL-13 with a STAT6-reliant pathway12,22
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- Abbreviations: CON, control; CANA, canagliflozin; AMPK, AMP-activated proteins kinase; ACC, acetyl-CoA carboxylase
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