Lipid Signaling in T Cell Development and Function

Editorial

10 August 2015

Editorial: Lipid Signaling in T Cell Development and Function

Karsten Sauer

and

Klaus Okkenhaug

5,020 views

1 citations

Editors

Karsten Sauer

Cullinan Oncology

Klaus Okkenhaug

University of Cambridge

Impact

Activation of class I PI3Ks by YxxM signaling subunits and GPCRs. Membrane receptors that activate PI3K include CD19, CD28, and NKG2D co-receptors, cytokine receptors (e.g., IL-2R), G-protein-coupled receptors (chemokine receptors), and Fcγ receptor I and III. Class IA PI3Ks are recruited to the plasma membrane through SH2 domain interactions with phosphorylated YxxM motifs. Class IB PI3Ks are recruited and activated by direct interaction with the Gβγ subunit following GPCR activation. Activated PI3K phosphorylates the membrane lipid PI(4,5)P2 to form PI(3,4,5)P3.

Review

13 March 2015

Lipid and Protein Co-Regulation of PI3K Effectors Akt and Itk in Lymphocytes

Xinxin Wang

, 1 more and

Yina Hsing Huang

13,179 views

35 citations

Schematic representation of the main biochemical pathways that mediate the production of mono-hydroxy fatty acids and leukotrienes (A), and the poly-hydroxy fatty acids lipoxins, resolvins, and protectins (B), products of transcellular metabolism. LOX, lipoxygenase; HETE, eicosatetraenoic acid; HEpETE, eicosaperoxytetraenoic acid; LT, leukotriene; acCOX-2, acetylated cyclooxygenase-2; CYP, cytochrome P450; LX, lipoxin; RvE, resolving series E; RvD, resolving series D; MaR, maresin.

Review

25 February 2014

Polyunsaturated Fatty Acid-Derived Lipid Mediators and T Cell Function

Anna Nicolaou

, 2 more and

Federica Marelli-Berg

12,964 views

62 citations

Review

18 October 2013

Role of Adipokines Signaling in the Modulation of T Cells Function

Claudio Procaccini

, 5 more and

Giuseppe Matarese

10,583 views

78 citations

Phosphoinositide signaling and its regulation by phosphatases. PI3K converts PI(4,5)P2 to a key secondary messenger PI(3,4,5)P3. Phosphatases like PTEN and SHIP1/2 regulate cellular levels of PI(3,4,5)P3 by hydrolyzing it to PI(4,5)P2 and PI (3,4)P2 respectively. PLCγ converts PI(4,5)P2 to IP3 and DAG. IP3 a soluble inositol phosphate is required for Ca2+ mobilization while DAG can activate the Ras-Raf-ERK1/2 pathway. IP3 3-Kinases convert IP3 to IP4, another important soluble inositol poly-phosphate that either positively or negatively regulates the binding of PI(3,4,5)P3 to PH-domain containing proteins. The SHIP1/2 product PI(3,4)P2 is hydrolyzed by INPP4A/B into PI(3)P by removal of the phosphate at the 4-position of the inositol ring. PI(3,4,5)P3 and/or PI(3,4)P2 enable recruitment to the plasma membrane of several PH-domain containing proteins including PDK1, AKT, BTK, ITK, and thus regulate pivotal cellular processes including activation, proliferation, and survival. PH-domain containing adaptor proteins (GABs, SKAPs, Bam32, and TAPP) can also bind to phosphoinositides and regulate cell signaling (indicated as green boxes). AKT, Protein Kinase B; PDK1, phosphoinositide-dependent kinase-1, PLCγ phospholipase Cγ; ITK, IL-2-inducible T cell kinase) and BTK, Bruton agammaglobulinemia tyrosine kinase.

Review

23 September 2013

Role of Inositol Poly-Phosphatases and Their Targets in T Cell Biology

Neetu Srivastava

, 1 more and

William Garrow Kerr

8,956 views

27 citations

Model of synergy between RasGRP and SOS in TCR signaling. TCR stimulation is connected to activation of RasGRP via tyrosine phosphorylation of the adapter molecule LAT and activation of PLCγ1, that metabolizes PIP2 into IP3 and DAG to trigger two second messenger pathways; Ca2+ and DAG. Activated RasGRP can enhance the full activation of SOS by providing Ras·GTP, allosterically activating SOS. In principle, the TCR-LAT-PLCγ1 pathway can also indirectly facilitate SOS activation via DAG; DGK metabolizes DAG and converts it to PA, which is a possible target for the HF and/or PH domains in SOS.

Review

04 September 2013

Regulation of Ras Exchange Factors and Cellular Localization of Ras Activation by Lipid Messengers in T Cells

Jesse E. Jun

, 1 more and

Jeroen P. Roose

16,066 views

66 citations

Schematic representation of the GroPIns metabolism. The formation of GroPIns occurs from membrane phosphatidylinositol (PtdIns) via two sequential steps, both of which are catalyzed by PLA2IVα. The first deacylation produces lysophosphatidylinositol (LysoPtdIns) and free arachidonic acid, since PLA2IVα selectively hydrolyzes phosphoinositides substituted in the sn-2 position with arachidonic acid (49). The second deacylation releases free fatty acid and GroPIns. As indicated, PLA2IVα supports both of these deacylation steps, as demonstrated in in vitro investigations using purified phosphoinositide and lysophosphatidylinositol substrates together with the recombinant enzyme (4). Once produced in the cytoplasm, GroPIns can be active on intracellular targets or can be released through the Glut2 transporter into the extracellular space, where it can act as a paracrine factor on nearby target cells. The subsequent catabolism of GroPIns is instead located on the extracellular side of the plasma-membrane and is mediated by the GDEs. GroPIns4P formation, also schematized, occurs starting from membrane phosphatidylinositol 4-phosphate which is hydrolyzed, as for GroPIns, by PLA2IVα (unpublished observations, see main text for details).

Perspective

29 July 2013

The Glycerophosphoinositols: From Lipid Metabolites to Modulators of T-Cell Signaling

Laura Patrussi

, 2 more and

Cosima T. Baldari

5,632 views

23 citations

Review

18 June 2013

The Vitamin D Receptor and T Cell Function

Martin Kongsbak

, 2 more and

Marina Rode von Essen

Proposed model for VDR signaling in T cells. Various extracellular signals including infection, inflammation, steroid and peptide hormones, and diet are involved in regulation of the intracellular VDR level. During an immune response the TCR is triggered by specific antigens, inducing a cascade of intracellular signaling events. Among these, lck and ZAP-70 are activated leading to activation of the p38 kinase which in naïve human T cells induce expression of VDR. TCR triggering also promotes expression of the 1,25(OH)2D3 synthesis enzyme CYP27B1. Through intrinsic synthesis of 1,25(OH)2D3 and uptake of 1,25(OH)2D3 from the extracellular environment, VDR is activated and translocated into the nucleus where it either induce or suppress transcription of a variety of genes. As an example, VDR induce upregulation of PLC-γ1 in naïve human T cells. Once PLC-γ1 is expressed, TCR induced activation of PLC-γ1 leads to activation of PKA and PKC and an increase in the intracellular calcium level. In other cell types PKA and PKC has been shown to modulate expression of VDR, depending on the particular cell type and cellular differentiation state investigated. An increase in intracellular calcium concentration activates NFAT1 a necessary transcription factor for expression of IL-2 and other cytokines. IL-2 is a cytokine required for proliferation of T cells and one mechanism by which VDR adjust T cell activity is to outcompete NFAT1’s binding to the IL-2 promoter and furthermore to down-regulate the actual expression of NFAT1. To control VDR activity a series of negative feedback loops exists; activated VDR both induce expression of the 1,25(OH)2D3 degrading enzyme CYP24A1 and down-regulates expression of the 1,25(OH)2D3 synthesizing enzyme CYP27B1.

The vitamin D receptor (VDR) is a nuclear, ligand-dependent transcription factor that in complex with hormonally active vitamin D, 1,25(OH)₂D₃, regulates the expression of more than 900 genes involved in a wide array of physiological functions. The impact of 1,25(OH)₂D₃-VDR signaling on immune function has been the focus of many recent studies as a link between 1,25(OH)₂D₃ and susceptibility to various infections and to development of a variety of inflammatory diseases has been suggested. It is also becoming increasingly clear that microbes slow down immune reactivity by dysregulating the VDR ultimately to increase their chance of survival. Immune modulatory therapies that enhance VDR expression and activity are therefore considered in the clinic today to a greater extent. As T cells are of great importance for both protective immunity and development of inflammatory diseases a variety of studies have been engaged investigating the impact of VDR expression in T cells and found that VDR expression and activity plays an important role in both T cell development, differentiation and effector function. In this review we will analyze current knowledge of VDR regulation and function in T cells and discuss its importance for immune activity.

60,384 views

274 citations