Sustained signaling leading to T cell activation results from prolonged T cell receptor occupancy. Role of T cell actin cytoskeleton.

Valitutti, Salvatore; Dessing, Mark C.; Aktories, Klaus; Gallati, H.; Lanzavecchia, Antonio

doi:10.1084/jem.181.2.577

Cited by 491 publications

(406 citation statements)

References 33 publications

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“…Our findings suggest that the impaired T cell-dependent responses may, at least in part, be due to the impaired capacity of the Bcl10-deficient cells to polymerize actin. This idea is consistent with our observation that T cell spreading and conjugate formation, both known to depend on TCR-induced actin polymerization (21,34,35,46,47), were affected in Bcl10-silenced cells.…”

Section: Discussionsupporting

confidence: 82%

Bcl10 Controls TCR- and FcγR-Induced Actin Polymerization

Azagra

Gaide

Ho³

et al. 2007

The Journal of Immunology

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Bcl10 plays an essential role in the adaptive immune response, because Bcl10-deficient lymphocytes show impaired Ag receptor-induced NF-κB activation and cytokine production. Bcl10 is a phosphoprotein, but the physiological relevance of this posttranslational modification remains poorly defined. In this study, we report that Bcl10 is rapidly phosphorylated upon activation of human T cells by PMA/ionomycin- or anti-CD3 treatment, and identify Ser138 as a key residue necessary for Bcl10 phosphorylation. We also show that a phosphorylation-deficient Ser138/Ala mutant specifically inhibits TCR-induced actin polymerization yet does not affect NF-κB activation. Moreover, silencing of Bcl10, but not of caspase recruitment domain-containing MAGUK protein-1 (Carma1) induces a clear defect in TCR-induced F-actin formation, cell spreading, and conjugate formation. Remarkably, Bcl10 silencing also impairs FcγR-induced actin polymerization and phagocytosis in human monocytes. These results point to a key role of Bcl10 in F-actin-dependent immune responses of T cells and monocytes/macrophages.

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Section: Discussionsupporting

confidence: 82%

Bcl10 Controls TCR- and FcγR-Induced Actin Polymerization

Azagra

Gaide

Ho³

et al. 2007

The Journal of Immunology

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“…However, one weakness of this initial study was its reliance on anti-CD3 stimulation. Interactions between the 2C11 anti-CD3⑀ and the TCR are of much higher affinity, with a much slower off-rate, than the typical interaction between peptide-bearing MHC molecules and the TCR (32,33). Furthermore, the original studies used responder cells that contained both naive and memory T cells; because aging leads to major increases in memory T cell numbers at the expense of naive T cells (for review see Ref.…”

Section: Single-cell Analyses Reveal Two Defects Inmentioning

confidence: 99%

Single-Cell Analyses Reveal Two Defects in Peptide-Specific Activation of Naive T Cells from Aged Mice

Garcia

Miller

2001

The Journal of Immunology

114

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Confocal fluorescent microscopy was used to study redistribution of membrane-associated proteins in naive T cells from young and old mice from a transgenic stock whose T cells express a TCR specific for a peptide derived from pigeon cytochrome C. About 50% of the T cells from young mice that formed conjugates with peptide-pulsed APC were found to form complexes, at the site of binding to the APC, containing CD3ε, linker for activation of T cells (LAT), and Zap-70 in a central area and c-Cbl, p95vav, Grb-2, PLCγ, Fyn, and Lck distributed more uniformly across the interface area. Two-color staining showed that those cells that were able to relocalize c-Cbl, LAT, CD3ε, or PLCγ typically relocalized all four of these components of the activation complex. About 75% of conjugates that rearranged LAT, c-Cbl, or PLCγ also exhibited cytoplasmic NF-AT migration to the T cell nucleus. Aging had two effects. First, it led to a diminution of ∼2-fold in the proportion of T cell/APC conjugates that could relocalize any of the nine tested proteins to the immune synapse. Second, aging diminished by ∼2-fold the frequency of cytoplasmic NF-AT migration among cells that could generate immune synapses containing LAT, c-Cbl, or PLCγ. Thus naive CD4 T cells from old mice exhibit at least two separable defects in the earliest stages of activation induced by peptide/MHC complexes.

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“…In cells treated with colchicine to disrupt microtubules, STIM1 localized to blebs that protruded from the top of the cell instead of forming a normal cap (Supplemental Figure S4, A and B). Evaluating the effects of disrupting the actin cytoskeleton was problematic because complete disassembly inhibits TCR activation, Ca 2ϩ flux and blocks spreading of T-cells (Valitutti et al, 1995;Bunnell et al, 2001;Tskvitaria-Fuller et al, 2003). We used a low dose of latrunculin to disrupt the actin network as visualized by actin-GFP (data not shown).…”

Section: An Intact Cytoskeleton Is Required For Normal Cap Formationmentioning

confidence: 99%

Dynamic Movement of the Calcium Sensor STIM1 and the Calcium Channel Orai1 in Activated T-Cells: Puncta and Distal Caps

Barr

Bernot

Srikanth

et al. 2008

MBoC

130

142

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The proteins STIM1 and Orai1 are the long sought components of the store-operated channels required in T-cell activation. However, little is known about the interaction of these proteins in T-cells after engagement of the T-cell receptor. We found that T-cell receptor engagement caused STIM1 and Orai1 to colocalize in puncta near the site of stimulation and accumulate in a dense structure on the opposite side of the T-cell. FRET measurements showed a close interaction between STIM1 and Orai1 both in the puncta and in the dense cap-like structure. The formation of cap-like structures did not entail rearrangement of the entire endoplasmic reticulum. Cap formation depended on TCR engagement and tyrosine phosphorylation, but not on channel activity or Ca 2؉ influx. These caps were very dynamic in T-cells activated by contact with superantigen pulsed B-cells and could move from the distal pole to an existing or a newly forming immunological synapse. One function of this cap may be to provide preassembled Ca 2؉ channel components to existing and newly forming immunological synapses. INTRODUCTIONT-cell activation in response to antigen induces and requires the elevation of intracellular Ca 2ϩ (Hogan et al., 2003;Quintana et al., 2005;Feske, 2007). T-cell receptor (TCR) engagement leads to activation of well-documented signal transduction pathways that cause a rapid release of Ca 2ϩ from the endoplasmic reticulum (ER; Samelson, 2002;Panyi et al., 2004;Gwack et al., 2007a). The depletion of Ca 2ϩ from this internal store then leads to the opening of ion channels in the plasma membrane (PM) allowing an influx of Ca 2ϩ from outside the cell. The store-operated channel responsible for Ca 2ϩ influx in T-cells is known as the Ca 2ϩ release-activated Ca 2ϩ (CRAC) channel, which has been studied by electrophysiological techniques for many years (Lewis, 2001;Prakriya and Lewis, 2003;Cahalan et al., 2007;Hewavitharana et al., 2007;Hogan and Rao, 2007;Putney, 2007a).Sustained elevation of cytosolic Ca 2ϩ is required for complete T-cell activation (Iezzi et al., 1998;Lewis, 2001;Hogan et al., 2003;Feske, 2007). High levels of intracellular Ca 2ϩ are necessary to maintain the interaction between a T-cell and antigen-presenting cell (APC) that leads to formation of the specialized contact surface known as the immunological synapse (IS). Increased Ca 2ϩ levels are also required for the activation of transcription factors. In particular, elevated Ca 2ϩ maintains prolonged nuclear accumulation of nuclear factor of activated T-cells (NFAT) by activating the phosphatase calcineurin that dephosphorylates NFAT, allowing it to translocate to the nucleus and activate genes such as IL2 (Hogan et al., 2003;Macian, 2005). Several hours of Ca 2ϩ influx are required to complete the T-cell activation program, which involves expression of a large number of activation-associated genes (Lewis, 2001;Macian et al., 2002;Hogan et al., 2003).Although sustained Ca 2ϩ influx in T-cells has been studied for decades, the proteins involved have only been ident...

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Sustained signaling leading to T cell activation results from prolonged T cell receptor occupancy. Role of T cell actin cytoskeleton.

Cited by 491 publications

References 33 publications

Bcl10 Controls TCR- and FcγR-Induced Actin Polymerization

Bcl10 Controls TCR- and FcγR-Induced Actin Polymerization

Single-Cell Analyses Reveal Two Defects in Peptide-Specific Activation of Naive T Cells from Aged Mice

Dynamic Movement of the Calcium Sensor STIM1 and the Calcium Channel Orai1 in Activated T-Cells: Puncta and Distal Caps

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