In the Immune Synapse, ZAP-70 Controls T Cell Polarization and Recruitment of Signaling Proteins but Not Formation of the Synaptic Pattern

Blanchard, Nicolas; Bartolo, Vincenzo Di; Hivroz, Claire

doi:10.1016/s1074-7613(02)00421-1

Cited by 121 publications

(140 citation statements)

References 48 publications

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“…5F). To verify that accumulation of clathrin, actin, dynamin-2, Arp2/3 complex, CD2AP and Hip1R at the IS was specific and to validate the Synapsis Measures software, we analyzed the cytoplasmic accumulation of GFP and CD45, a membrane tyrosine phosphatase, which after initial cell-cell contact does not accumulate at the IS (Blanchard et al, 2002;Freiberg et al, 2002;Varma et al, 2006), in T-cell-APC conjugates in the presence and absence of antigen. Endogenous CD45 and GFP did not accumulate at the IS after antigen stimulation in control or clathrin KD T cells (supplementary material Fig.…”

Section: Clathrin Is Necessary For Recruitment Of Key Adaptor and Regmentioning

confidence: 99%

Endosomal clathrin drives actin accumulation at the immunological synapse

Calabia-Linares

Robles‐Valero

Fuente

et al. 2011

Journal of Cell Science

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SummaryAntigen-specific cognate interaction of T lymphocytes with antigen-presenting cells (APCs) drives major morphological and functional changes in T cells, including actin rearrangements at the immune synapse (IS) formed at the cell-cell contact area. Here we show, using cell lines as well as primary cells, that clathrin, a protein involved in endocytic processes, drives actin accumulation at the IS. Clathrin is recruited towards the IS with parallel kinetics to that of actin. Knockdown of clathrin prevents accumulation of actin and proteins involved in actin polymerization, such as dynamin-2, the Arp2/3 complex and CD2AP at the IS. The clathrin pool involved in actin accumulation at the IS is linked to multivesicular bodies that polarize to the cell-cell contact zone, but not to plasma membrane or Golgi complex. These data underscore the role of clathrin as a platform for the recruitment of proteins that promote actin polymerization at the interface of T cells and APCs.

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Section: Clathrin Is Necessary For Recruitment Of Key Adaptor and Regmentioning

confidence: 99%

Endosomal clathrin drives actin accumulation at the immunological synapse

Calabia-Linares

Robles‐Valero

Fuente

et al. 2011

Journal of Cell Science

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“…In T cells, ZAP-70 is known to be required for clustering signaling molecules into lipid rafts. 20 We assumed that the expression of ZAP-70 in a subset of CLL patients might also effect the activation of signaling molecules associated with the B-cell receptor.…”

Section: Pkc-bii Is Constitutively Expressed Within Lipid-rafts In Zamentioning

confidence: 99%

Recruitment of PKC-βII to lipid rafts mediates apoptosis-resistance in chronic lymphocytic leukemia expressing ZAP-70

et al. 2009

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ZAP-70 is a key signaling molecule in T cells. It couples the antigen-activated T-cell receptor to downstream signaling pathways. Its expression in leukemic B-cells derived from a subgroup of patients with chronic lymphocytic leukemia (CLL) is associated with an aggressive course of the disease. However, its implication for the pathogenesis of aggressive CLL is still unclear. In this study, we show that the expression of ZAP-70 enhances the signals associated with the B-cell receptor, recruiting protein kinase C-bII (PKC-bII) into lipid raft domains. Subsequently, PKC-bII is activated and shuttles from the plasma membrane to the mitochondria. We unravel that the antiapoptotic protein Bcl-2 and its antagonistic BH3-protein Bim EL are putative substrates for PKC-bII. PKC-bII-mediated phosphorylation of Bcl-2 augments its antiapoptotic function by increasing its ability to sequester more pro-apoptotic Bim EL. In addition, the phosphorylation of Bim EL by PKC-bII leads to its proteasomal degradation. These changes confer leukemic cells to a more antiapoptotic state with aggressiveness of the disease. Most importantly, these molecular changes can be therapeutically targeted with the small molecule inhibitor Enzastaurin. We provide evidence that this compound is highly active in leukemic cells and augments the cytotoxic effects of standard chemotherapeutic drugs.

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“…CD45 (ϩ3.7) is tyrosine phosphatase required for lymphocyte activation. Zap70 (T cell receptor -chain associated protein kinase, 70 kDa, ϩ3.1) plays a vital signaling role in the interaction between antigen presenting cells and T cells that leads to T cell activation (19). T cell factor 1 (ϩ8.4) is critical for T cell maturation (20), whereas B lymphoid kinase (ϩ2.2) is important for B cell proliferation and developmental progression (21).…”

Section: Molecular Characterization Of the Host Response At The Fs͞z mentioning

confidence: 99%

The impact of parietal cells onHelicobacter pyloritropism and host pathology: An analysis using gnotobiotic normal and transgenic mice

Syder

Guruge

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Helicobacter pylori infection of the human stomach is common and typically benign, although a subset of hosts develops severe pathology. Infection occurs in an organ with distinct microenvironments characterized by pronounced differences in the composition of acid-producing parietal cells. In this study, we examine determinants of bacterial tropism to various gastric niches by using germ-free normal and transgenic mice with an engineered parietal cell ablation. Mice were colonized for 8 weeks with a clinical isolate (Hp1) that expresses adhesins recognized by epithelial NeuAc␣2,3Gal␤1,4 glycan receptors. In normal mice, Hp1 has tropism for a parietal cell-deficient niche where sialylated glycans are expressed by a narrow band of pit cells positioned at the boundary between the squamous epithelium (forestomach) and the proximal glandular epithelium. Lymphoid aggregates that develop in this niche, but not elsewhere in the stomach, were analyzed by GeneChip and quantitative RT-PCR studies of laser capture microdissected mucosa and yielded a series of biomarkers indicative of immune cell activation and maturation. Genetic ablation of parietal cells produced a new source of NeuAc␣2,3Gal␤1,4 glycans in amplified gastric epithelial lineage progenitors, with accompanying expansion of Hp1 within the glandular epithelium. Lymphoid aggregates that develop in this formerly acid-protected epithelium have molecular features similar to those observed at the forestomach͞glandular junction. These findings demonstrate the important roles played by parietal cells and glycan receptors in determining the positioning of H. pylori within the gastric ecosystem, and emphasize the need to consider the evolution of pathology within a given host in a niche-specific context. gastric acid ͉ adhesin receptors ͉ immune response ͉ germ-free animals A t least half of all humans harbor Helicobacter pylori in their stomachs. This microaerophilic bacterium is usually acquired in childhood and remains in the stomach of its host for decades (1). In most cases, the host-microbial relationship is benign, marked only by mild mucosal inflammation. However, in a subset of individuals, this relationship evolves to produce gastric or duodenal ulcers, adenocarcinoma, or mucosal lymphoma (2).Lee and coworkers (3) have emphasized that severe pathology more often develops in regions of the gastric epithelium where there is a marked transition in the census of acid-producing parietal cells. They and others proposed that local environmental pH gradients at these transitions provide the organism with an opportunity to sample and occupy niches where growth conditions are optimal (3, 4). Once the organism becomes entrenched, pH and other niche-associated factors (e.g., redox state, nutrient availability) then presumably shape the nature of the host-microbial interaction (5).These speculations emphasize the importance of viewing the nature of the host-microbial cross-talk, the genetic microevolution of this bacterium (6, 7), and the structure of the pathogenic cascad...

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In the Immune Synapse, ZAP-70 Controls T Cell Polarization and Recruitment of Signaling Proteins but Not Formation of the Synaptic Pattern

Cited by 121 publications

References 48 publications

Endosomal clathrin drives actin accumulation at the immunological synapse

Endosomal clathrin drives actin accumulation at the immunological synapse

Recruitment of PKC-βII to lipid rafts mediates apoptosis-resistance in chronic lymphocytic leukemia expressing ZAP-70

The impact of parietal cells onHelicobacter pyloritropism and host pathology: An analysis using gnotobiotic normal and transgenic mice

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