Hasil untuk "hep-lat"

Michel-Pierre Coll, Hannah Hobson, G. Bird et al.

The Heartbeat Evoked Potential (HEP) has been proposed as a neurophysiological marker of interoceptive processing. Despite its use to validate interoceptive measures and to assess interoceptive functioning in clinical groups, the empirical evidence for a relationship between HEP amplitude and interoceptive processing, including measures of such processing, is scattered across several studies with varied designs. The aim of this systematic review and meta-analysis was to examine the body of HEP-interoception research, and consider the associations the HEP shows with various direct and indirect measures of interoception, and how it is affected by manipulations of interoceptive processing. Specifically, we assessed the effect on HEP amplitude of manipulating attention to the heartbeat; manipulating participants' arousal; the association between the HEP and behavioural measures of cardiac interoception; and comparisons between healthy and clinical groups. Following database searches and screening, 45 studies were included in the systematic review and 42 in the meta-analyses. We noted variations in the ways individual studies have attempted to address key confounds, particularly the cardiac field artefact. Meta-analytic summaries indicated there were moderate to large effects of attention, arousal, and clinical status on the HEP, and a moderate association between HEP amplitude and behavioural measures of interoception. Problematically, the reliability of the meta-analytic effects documented here remain unknown, given the lack of standardised protocols for measuring the HEP. Thus, it is possible effects are driven by confounds such as cardiac factors or somatosensory effects.

John C. Zwaagstra, H. Ghiasi, S. Slanina et al.

B. Wilson, J. Pfeiffer, Z. Surviladze et al.

In mast cells, cross-linking the high-affinity IgE receptor (FcεRI) initiates the Lyn-mediated phosphorylation of receptor ITAMs, forming phospho-ITAM binding sites for Syk. Previous immunogold labeling of membrane sheets showed that resting FcεRI colocalize loosely with Lyn, whereas cross-linked FcεRI redistribute into specialized domains (osmiophilic patches) that exclude Lyn, accumulate Syk, and are often bordered by coated pits. Here, the distribution of FcεRI β is mapped relative to linker for activation of T cells (LAT), Grb2-binding protein 2 (Gab2), two PLCγ isoforms, and the p85 subunit of phosphatidylinositol 3-kinase (PI3-kinase), all implicated in the remodeling of membrane inositol phospholipids. Before activation, PLCγ1 and Gab2 are not strongly membrane associated, LAT occurs in small membrane clusters separate from receptor, and PLCγ2, that coprecipitates with LAT, occurs in clusters and along cytoskeletal cables. After activation, PLCγ2, Gab2, and a portion of p85 colocalize with FcεRI β in osmiophilic patches. LAT clusters enlarge within 30 s of receptor activation, forming elongated complexes that can intersect osmiophilic patches without mixing. PLCγ1 and another portion of p85 associate preferentially with activated LAT. Supporting multiple distributions of PI3-kinase, FcεRI cross-linking increases PI3-kinase activity in anti-LAT, anti-FcεRIβ, and anti-Gab2 immune complexes. We propose that activated mast cells propagate signals from primary domains organized around FcεRIβ and from secondary domains, including one organized around LAT.

P. Paz, Su Wang, H. Clarke et al.

Joseph Lin, A. Weiss, T. Finco

LAT, a transmembrane adapter protein found in glycolipid-enriched microdomains (GEMs), is essential for T cell activation. In this study, we have utilized a LAT-deficient mutant of the Jurkat T cell line, J.CaM2, to explore various requirements for LAT function. First, we demonstrate that LAT must be present in GEMs for coupling T cell receptor (TCR) engagement to activation of the Ras signaling pathway, increases in intracellular Ca2+, and induction of the transcription factor nuclear factor of activated T cells (NF-AT). Second, we show that the extracellular and transmembrane domains of LAT are dispensable for these TCR-mediated events once LAT has localized to GEMs. These results provide important insights into both the structural domains of LAT and its subcellular localization that are required for effective TCR signaling.

Anne L Astier, M. Trescol-Biémont, O. Azocar et al.

M. Zeyda, G. Staffler, V. Hořejší et al.

Polyunsaturated fatty acids (PUFAs) suppress immune responses and inhibit T cell activation through largely unknown mechanisms. The displacement of signaling proteins from membrane lipid rafts has recently been suggested as underlying PUFA-mediated T cell inhibition. We show here that PUFA treatment specifically interferes with T cell signal transduction by blocking tyrosine phosphorylation of LAT (linker for activation of T cells) and phospholipase Cγ1. A significant fraction of LAT was displaced from rafts by PUFA treatment along with other signaling proteins. However, retaining LAT alone in lipid rafts effectively restored phospholipase Cγ1/calcium signaling in PUFA-treated T cells. These data reveal LAT displacement from lipid rafts as a molecular mechanism by which PUFAs inhibit T cell signaling and underline the predominant importance of LAT localization in rafts for efficient T cell activation.

T. Harder, Marina Kuhn

Activation of T cell antigen receptor (TCR) induces tyrosine phosphorylations that mediate the assembly of signaling protein complexes. Moreover, cholesterol-sphingolipid raft membrane domains have been implicated to play a role in TCR signal transduction. Here, we studied the assembly of TCR with signal transduction proteins and raft markers in plasma membrane subdomains of Jurkat T leukemic cells. We employed a novel method to immunoisolate plasma membrane subfragments that were highly concentrated in activated TCR–CD3 complexes and associated signaling proteins. We found that the raft transmembrane protein linker for activation of T cells (LAT), but not a palmitoylation-deficient non-raft LAT mutant, strongly accumulated in TCR-enriched immunoisolates in a tyrosine phosphorylation–dependent manner. In contrast, other raft-associated molecules, including protein tyrosine kinases Lck and Fyn, GM1, and cholesterol, were not highly concentrated in TCR-enriched plasma membrane immunoisolates. Many downstream signaling proteins coisolated with the TCR/LAT-enriched plasma membrane fragments, suggesting that LAT/TCR assemblies form a structural scaffold for TCR signal transduction proteins. Our results indicate that TCR signaling assemblies in plasma membrane subdomains, rather than generally concentrating raft-associated membrane proteins and lipids, form by a selective protein-mediated anchoring of the raft membrane protein LAT in vicinity of TCR.

G. Perng, H. Ghiasi, S. Slanina et al.

T. Finco, T. Kadlecek, W. Zhang et al.

J. Gibbins, S. Briddon, A. Shutes et al.

There is extensive evidence to show that phosphatidylinositol 3-kinase plays an important role in signaling by the immune family of receptors, which has recently been extended to include the platelet collagen receptor, glycoprotein VI. In this report we present two potential mechanisms for the regulation of this enzyme on stimulation of platelets by collagen. We show that on stimulation with collagen, the regulatory subunit of phosphatidylinositol 3-kinase associates with the tyrosine-phosphorylated form of the adapter protein linker for activator of T Cells (LAT) and the tyrosine-phosphorylated immunoreceptor tyrosine-based activation motif of the Fc receptor γ-chain (a component of the collagen receptor complex that includes glycoprotein VI). The associations of the Fc receptor γ-chain and LAT with p85 are rapid and supported by the Src-homology 2 domains of the regulatory subunit. We did not obtain evidence to support previous observations that the regulatory subunit of phosphatidylinositol 3-kinase is regulated through association with the tyrosine kinase Syk. The present results provide a molecular basis for the regulation of the p85/110 form of phosphatidylinositol 3-kinase by GPVI, the collagen receptor that underlies activation.

L. Balagopalan, V. Barr, C. Sommers et al.

Nicole J. Kubat, A. Amelio, Nicole V Giordani et al.

A. Bertke, Amita Patel, Y. Imai et al.

G. Bonello, N. Blanchard, M. Montoya et al.

S. Koonpaew, Shudan Shen, L. Flowers et al.

Engagement of the T cell receptor for antigen (TCR) induces formation of signaling complexes mediated through the transmembrane adaptor protein, the linker for activation of T cells (LAT). LAT plays an important role in T cell development, activation, and homeostasis. A knock-in mutation at Tyr136, which is the phospholipase C (PLC)-γ1–binding site in LAT, leads to a severe autoimmune disease in mice. In this study, we show that CD4+CD25+ T reg cells that expressed Foxp3 transcription factor were nearly absent in both thymus and peripheral lymphoid organs of LATY136F mice. This defect was not a result of the autoimmune environment as LATY136F T reg cells also failed to develop in healthy LAT−/− mice that received mixed wild-type and LATY136F bone marrow cells. Moreover, adoptive transfer of normal CD4+CD25+ T reg cells protected neonatal LATY136F mice from developing this disease. These T reg cells effectively controlled expansion of CD4+ T cells in LATY136F mice likely via granzymes and/or TGF-β–mediated suppression. Furthermore, ectopic expression of Foxp3 conferred a suppressive function in LATY136F T cells. Our data indicate that the LAT–PLC-γ1 interaction plays a critical role in Foxp3 expression and the development of CD4+CD25+ T reg cells

J. Haskey

Yu-Wen Su, H. Jumaa

M. Hundt, H. Tabata, Myung-Shin Jeon et al.

Lucinda F. Reynolds, Carine de Bettignies, T. Norton et al.

Vav1 is a signaling protein required for both positive and negative selection of CD4+CD8+ double positive thymocytes. Activation of the ERK MAPK pathway is also required for positive selection. Previous work has shown that Vav1 transduces T cell receptor (TCR) signals leading to an intracellular calcium flux. We now show that in double positive thymocytes Vav1 is required for TCR-induced activation of the ERK1 and ERK2 kinases via a pathway involving the Ras GTPase, and B-Raf, MEK1, and MEK2 kinases. Furthermore, we show that Vav1 transduces TCR signals to Ras by controlling the membrane recruitment of two guanine nucleotide exchange factors. First, Vav1 transduces signals via phospholipase Cγ1 leading to the membrane recruitment of RasGRP1. Second, Vav1 is required for recruitment of Sos1 and -2 to the transmembrane adapter protein LAT. Finally, we show that Vav1 is required for TCR-induced LAT phosphorylation, a key event for the activation of both phospholipase Cγ1 and Sos1/2. We propose that reduced LAT phosphorylation is the key reason for defective TCR-induced calcium flux and ERK activation in Vav1-deficient cells.