Positive and negative regulation by SLP-76/ADAP and Pyk2 of chemokine-stimulated T-lymphocyte adhesion mediated by integrin α4β1

Dios‐Esponera, Ana; Val, Soledad Isern de; Sevilla-Movilla, Silvia; García-Verdugo, Rosa; García‐Bernal, David; Arellano‐Sánchez, Nohemí; Cabañas, Carlos; Teixidó, Joaquı́n

doi:10.1091/mbc.e14-07-1246

Cited by 10 publications

(14 citation statements)

References 86 publications

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“…This might appear similar to a previous study with human T cell lines and peripheral blood T cells, demonstrating that Pyk2 inhibition results in increased early adhesion to fibronectin or VCAM-1 after chemokine stimulation (19). This was shown to be due to an increase in the affinity of the integrin receptor, a 4 b 1 (19). In contrast, the increased spreading we observed with CTL occurred much later and in the absence of chemokine stimulation (Fig.…”

Section: Discussionsupporting

confidence: 91%

“…We were unable to examine a 4 b 1 function because mouse CTL do not express this integrin (12). Interestingly, although not a focus of their study, this same group did show that knockdown of Pyk2 in Molt-4 cells had no impact on cell adhesion to ICAM-1 in either the absence or presence of chemokine at early time points (19). Although they saw no increase in adhesion, they also detected no decrease in adhesion upon Pyk2 knockdown, which contrasts with our results with CTL as well as a previous study examining naive CD8 + T cells (17).…”

Section: Discussionmentioning

confidence: 94%

“…With respect to adhesion, Pyk2 negatively regulates adhesion of human T cell lines and peripheral blood T cells to fibronectin and VCAM-1, but not ICAM-1, in the presence of chemokines (19). In contrast, Pyk2 positively regulates naive mouse CD8 T cell (17) and NK cell (20) adhesion to ICAM-1, and has no impact on neutrophil (16) or eosinophil (21) adhesion.…”

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confidence: 95%

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Pyk2 Controls Integrin-Dependent CTL Migration through Regulation of De-Adhesion

Cheung

Ostergaard

2016

The Journal of Immunology

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Protein tyrosine kinase 2 (Pyk2) is required for T cell adhesion to ICAM-1; however, the mechanism by which it regulates adhesion remains unexplored. Pyk2 function in murine CTL clones and activated ex vivo CD8+ T cells was disrupted by pharmacological inhibition, knockdown of expression with small interfering RNA, or expression of the dominant-negative C-terminal domain. We found that Pyk2 is not absolutely required for adhesion of CTL to ICAM-1, but rather delays the initial adhesion. Disruption of Pyk2 function caused cells to display an unusual elongated appearance after 1 h on ICAM-1, consistent with abnormally strong adhesion. Furthermore, the random mobility of CTL on ICAM-1 was severely compromised using all three methods of disrupting Pyk2 function. Live-cell imaging studies revealed that the decreased migration is the result of a defect in the detachment from ICAM-1 at the trailing edge when Pyk2 function is inhibited. Examination of Pyk2 tyrosine phosphorylation in normal polarized cells demonstrated that Pyk2 phosphorylated at Y579 and Y580 preferentially localizes to the leading edge, whereas Y881-phosphorylated Pyk2 is enriched at the trailing edge, suggesting that the tyrosine phosphorylation of Pyk2 is spatially regulated in migrating CTL. Additionally, inhibition of Pyk2 caused cells to form multiple LFA-1–rich tails at the trailing edge, most likely resulting from a defect in LFA-1 release required for forward movement. Our results show that Pyk2 contributes to CTL migration by regulating detachment of CTL at the trailing edge, which could explain why Pyk2 is important for chemotactic and migratory responses.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 94%

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Pyk2 Controls Integrin-Dependent CTL Migration through Regulation of De-Adhesion

Cheung

Ostergaard

2016

The Journal of Immunology

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“…Together with SKAP55, to which a fraction is constitutively bound and to which it also stabilizes [7][8][9][10], ADAP facilitates a conformational change and hence, activation of integrins, a process known as inside-out signaling. Furthermore, the ADAP/SKAP55 module mediates signals generated from the interaction of integrins with their ligands on other cells, known as outside-in signaling [6,9,[11][12][13]. This is a prerequisite for firm adhesion, necessary not only in transmigration but also in formation of the immunologic synapse during the contact between naïve T cells and APCs [14,15].…”

Section: Introductionmentioning

confidence: 99%

“…This is a prerequisite for firm adhesion, necessary not only in transmigration but also in formation of the immunologic synapse during the contact between naïve T cells and APCs [14,15]. Furthermore, it has also been reported that ADAP is involved in the integrin signaling downstream of chemokine receptors, such as CCR7 and CXCR4; hence, its mediator role is not exclusively restricted to TCR signaling [12,15].…”

Section: Introductionmentioning

confidence: 99%

ADAP plays a pivotal role in CD4+ T cell activation but is only marginally involved in CD8+ T cell activation, differentiation, and immunity to pathogens

Parzmair

Gereke

Haberkorn

et al. 2016

Journal of Leukocyte Biology

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The adhesion and degranulation promoting adaptor protein (ADAP) is a multifunctional scaffold involved in many different signaling pathways that are important for the function of T cells, including the inside-out and outside-in signaling of integrins, the activation of NF-κB, and the subsequent production of proinflammatory cytokines (e.g., IFN-γ and IL-2). Strikingly, despite its well-established role in T cells, previous studies did not distinguish between CD4 and CD8 T cells, and thus, it is unknown whether ADAP fulfills equally important functions in both T cell subsets. We show here that despite comparable ADAP expression levels in CD4 and CD8 T cells, their function is differentially dependent on ADAP. Whereas in vitro TCR-stimulation experiments revealed that activation, proliferation, and adhesion are severely compromised in CD4 T cells lacking ADAP, their CD8 counterparts are hardly affected by ADAP deficiency. Accordingly, antigen-specific in vivo stimulation of adoptively transferred CD8 T cells during Listeria monocytogenes (Lm) and influenza A virus (IAV) infection revealed only moderate effects of ADAP deficiency in terms of CD8 T cell activation, proliferation, and differentiation, which, however, did not impair pathogen-specific immunity. Thus, we show for the first time that ADAP fulfills different functions in CD4 and CD8 T cells, with CD8 T cells being less dependent on ADAP. Our data identify ADAP as a potential molecular target for T cell subset-specific therapeutic interventions.

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VAV1 as a putative therapeutic target in autoimmune and chronic inflammatory diseases

Neurath,

Berg

2024

Trends in Immunology

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Positive and negative regulation by SLP-76/ADAP and Pyk2 of chemokine-stimulated T-lymphocyte adhesion mediated by integrin α4β1

Cited by 10 publications

References 86 publications

Pyk2 Controls Integrin-Dependent CTL Migration through Regulation of De-Adhesion

Pyk2 Controls Integrin-Dependent CTL Migration through Regulation of De-Adhesion

ADAP plays a pivotal role in CD4+ T cell activation but is only marginally involved in CD8+ T cell activation, differentiation, and immunity to pathogens

VAV1 as a putative therapeutic target in autoimmune and chronic inflammatory diseases

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