Lipid Signaling in T-Cell Development and Function

Abstract

Second messenger molecules relay, amplify, and diversify cell surface receptor signals. Two important examples are phosphorylated D-myo-inositol derivatives, such as phosphoinositide lipids within cellular membranes, and soluble inositol phosphates. Here, we review how phosphoinositide metabolism generates multiple second messengers with important roles in T-cell development and function. They include soluble inositol(1,4,5)trisphosphate, long known for its Ca 2þ -mobilizing function, and phosphatidylinositol(3,4,5)trisphosphate, whose generation by phosphoinositide 3-kinase and turnover by the phosphatases PTEN and SHIP control a key "hub" of TCR signaling. More recent studies unveiled important second messenger functions for diacylglycerol, phosphatidic acid, and soluble inositol(1,3,4,5)tetrakisphosphate (IP 4 ) in immune cells. Inositol(1,3,4,5)tetrakisphosphate acts as a soluble phosphatidylinositol(3,4,5)trisphosphate analog to control protein membrane recruitment. We propose that phosphoinositide lipids and soluble inositol phosphates (IPs) can act as complementary partners whose interplay could have broadly important roles in cellular signaling.S econd messenger molecules relay, amplify, and diversify signals perceived by cell surface receptors. One important second messenger family is comprised of the phosphorylated derivatives of the small cyclic poly-alcohol Dmyo-inositol. They include phosphoinositide lipids within cellular membranes, and soluble inositol phosphates, here termed IPs. In most stimulatory cells, the plasma membrane phosphoinositide, phosphatidylinositol(4,5)bisphosphate (here termed PIP 2 for improved readability, although several different PIP 2 isomers exist) is a key precursor for both other phosphoinositides and soluble IPs. Many of these regulate distinct and overlapping down-

Antiviral Regulation in Porcine Monocytic Cells at Different Activation States

“…We began our investigation by targeting pathways that modulate inflammation, antiviral states, and T-cell proliferation. Because of the importance of lipid signaling in regulation of inflammation and overall immune responses, we first screened mediators that regulate lipid metabolism (49)(50)(51). Among multiple selected agonists and antagonists for enzymes in lipid metabolism, 5-(tetradecyloxy)-2-furoic acid (ToFA), a competitive inhibitor of acetylCoA carboxylase (ACC) (40), significantly suppressed PRRSV infection in all cells tested (Fig.…”

Characterization of an arachidonic acid-deficient (Fads1 knockout) mouse model

“…As membrane phospholipid PI(4,5)P 2 is a key node of second messenger metabolism in T cells ( 12 ) and its acyl backbone is predominantly composed of 1-stearoyl-2-arachidonoyl species, we examined whether the absence of AA associated with the deletion of the Fads1 gene altered the PI(4,5)P 2 concentration in CD4 + T cells. The basal level of PI(4,5)P 2 was signifi cantly ( P < 0.05) decreased by approximately 24% in Fads1 Null CD4 + T cells compared with Het and Wt siblings ( Fig.…”

“…In addition to its role in cytokine regulation, AA is a major constituent of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ), and via the action of phospholipase C, results in the accumulation of inositol trisphosphate (IP 3 ) and 1-stearoyl-2-AA-diacylglycerol to elicit intracellular Ca 2+ mobilization ( 10 ). The hydrolysis of PI(4,5)P 2 plays an important role in membrane rapid cytoskeletal remodeling ( 11 ) and Ras/Erk, as well as Ca 2+ signaling in lymphocytes ( 12 ).…”

Tripartite motif containing protein 27 negatively regulates CD4 T cells by ubiquitinating and inhibiting the class II PI3K-C2β

“…In general, members of this family have been divided into three classes (I, II, III) based on sequence homology and substrate specificity (2)(3)(4). Most of the previous work on PI3Ks in lymphocyte activation have focused on the class I PI3Ks (p110 α, β, γ, and δ), which are responsible for the acute rise in PI(3,4,5)P 3 following antigen-receptor activation (5,6). Studies in knockout mice have demonstrated that p110δ and p110γ play partly redundant functions in T-cell activation, and are most important for T-cell receptor (TCR) signaling by peripheral T cells, as well as for T-cell development and survival (7)(8)(9)(10)(11).…”