Specific Patterns of Cdc42 Activity Are Related to Distinct Elements of T Cell Polarization

Tskvitaria-Fuller, Irina; Seth, Abhinav; Mistry, Neeta; Gu, Hua; Rosen, Michael K.; Wülfing, Christoph

doi:10.4049/jimmunol.177.3.1708

Cited by 50 publications

(53 citation statements)

References 37 publications

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“…Cdc42 regulates lamellipodial actin spreading (37) as well as phagocytosis (38) and macropinocytosis (44). When we blocked lamellipodial actin spreading with 100 nM dominant-negative Cdc42 as a protein transduction reagent (Cdc42dn) (37), only 31% of the T cell/APC couples showed CD48iGFP APC extensions as opposed to 69% with buffer only ( p Ͻ 0.001). As a control, 100 nM Rac1dn interfered neither with lamellipodial actin spreading (37) nor with CD48iGFP membrane extensions (67% of the cell couples displayed them).…”

Section: Characterization Of the T Cell Invagination As Lamellipodialmentioning

confidence: 99%

“…5B). None of five other tat fusion proteins tested (tat WASP VCA (17), N17 dominant-negative Rac1 (36), N17 dominant-negative Cdc42 (36), the WASP GTPase-binding domain (37), or V12 constitutively active Cdc42 (36)) showed a significant enhancement, establishing specificity. Cytohesin-1 has been linked to the regulation of LFA-1 avidity (18).…”

Section: Characterization Of the T Cell Invagination As Regulated Simmentioning

confidence: 99%

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A Large T Cell Invagination with CD2 Enrichment Resets Receptor Engagement in the Immunological Synapse

Singleton

Parvaze

Dama

et al. 2006

The Journal of Immunology

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T cell activation is driven by the TCR and complemented by costimulation. We have studied the dynamics of ligand-engagement of the costimulatory receptor CD2 in T cell/APC couples. Thousands of ligand-engaged CD2 molecules were included in a large T cell invagination at the center of the cellular interface within 1 min of cell couple formation. The structure and regulation of this invagination shared numerous features with phagocytosis and macropinocytosis. Three observations further characterize the invagination and the inclusion of CD2: 1) numerous ligand-engaged receptors were enriched in and internalized through the T cell invagination, none as prominently as CD2; 2) dissolution of the T cell invagination and CD2 engagement were required for effective proximal T cell signaling; and 3) the T cell invagination was uniquely sensitive to the affinity of the TCR for peptide-MHC. Based on this characterization, we speculate that the T cell invagination, aided by CD2 enrichment, internalizes parts of the TCR signaling machinery to reset T cell signaling upon agonist-mediated, stable APC contact.

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Section: Characterization Of the T Cell Invagination As Lamellipodialmentioning

confidence: 99%

Section: Characterization Of the T Cell Invagination As Regulated Simmentioning

confidence: 99%

A Large T Cell Invagination with CD2 Enrichment Resets Receptor Engagement in the Immunological Synapse

Singleton

Parvaze

Dama

et al. 2006

The Journal of Immunology

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“…S3A), critical regulator of cytoskeletal dynamics and cellular polarization. To address its role in cytolytic effector polarization, we investigated the intensity, transience, and patterns of active Cdc42 at the cytolytic effector/target cell interface using live cell imaging of a retrovirally expressed biosensor for active Cdc42 (25,27). As the function of the closely related Rho GTPase family member Rac has previously been studied (16), we will address Rac only (SI Text and Figs.…”

Section: Transient and Central Accumulation Of Active Cdc42 At The Inmentioning

confidence: 99%

“…First, the intensity of the interface accumulation of actin or signaling sensors at the population level is governed by two factors, the percentage of cytolytic effectors that show interface accumulation beyond a threshold and the amount of cellular actin or signaling sensor that is moved to the effector/target cell interface in the portion of the population that does shown accumulation. Therefore, to measure interface accumulation at the population level, the percentage of cell couples with interface accumulation was multiplied by the average fraction of actin or the signaling sensor that is translocated to the interface (25). This number thus gives the population-averaged percentage of cellular actin or signaling sensor that is moved to the effector/target cell interface and is used throughout the manuscript.…”

Section: Transient Polarization Of Cytolytic Effectors Is Coupled To mentioning

confidence: 99%

“…Later reductions in Cdc42 activity and actin accumulation at the cytolytic effector/target cell interface likely allow dissociation of nonproductive cell couples. To test this notion, we interfered with Cdc42 activation (24,25) such that initial polarization was preserved while sustained actin accumulation was blocked. This enhanced the frequency of cytolytic effectors involved in killing and secretion of IFN-γ.…”

mentioning

confidence: 99%

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Transience in polarization of cytolytic effectors is required for efficient killing and controlled by Cdc42

Sinai¹,

Nguyen²,

Schatzle³

et al. 2010

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

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Cytolytic effectors polarize toward target cells for effective killing and IFN-γ secretion. The spatiotemporal features of this polarization and their importance for cytolysis have not been resolved. In cytotoxic T cells and natural killer (NK) cells, transient polarization was consistently associated with effective killing. Polarization was regulated by Cdc42, a small Rho family GTPase universally critical for cytoskeletal dynamics. Transient accumulation of active Cdc42 at the cytolytic effector/target cell interface and focus of such accumulation on the interface center were closely related to cytolysis. Surprisingly, however, the intensity of Cdc42 activation was not. We interfered with Cdc42 activation in NK cells such that sustained polarization in long lasting nonkilling cell couples was selectively blocked. Thus the proportion of the NK cell population displaying transient polarization was increased. As a consequence, cytolytic responder frequency and IFN-γ production were enhanced upon such interference with Cdc42 activation. These data support the notion that transience in polarization is critical for cytolytic effector function, likely by preventing cytolytic effectors from becoming trapped in nonproductive target cell interactions. Each can also secrete IFN-γ to modulate adaptive immune function. To acquire effector capability, cytolytic effectors need to be primed. CTL priming occurs as the consequence of naive CD8 T cell interactions with antigen-presenting dendritic cells. NK cell priming requires cytokines generated predominantly by dendritic cells. However, the nature of the cytokines involved is less certain. IL-12 and IL-18 enable NK cells to secrete IFN-γ (1, 2) and are synergistic (3). IL-15 can promote NK cell expansion (4, 5). IL-15 needs transpresentation by the IL-15 receptor α chain (6, 7), which is induced on dendritic cells by engagement of Toll-like receptors (7). High concentrations of IL-2 effectively prime NK cells in vitro, as often used in clinical settings (8, 9). However, in vivo, IL-2 is dispensable for NK cell priming (5). To understand the role of the polarization of cytolytic effector in their function, the effect of priming conditions on NK cell polarization needs to be taken into account.Target cell contact triggers the complex polarization of primed cytolytic effectors, recruitment of cytolytic granules to the interface (10, 11), cytoskeletal reorientation (12, 13), and receptor clustering (14,15). Cytolytic effector polarization is likely functionally important, as key regulators of cytoskeletal dynamics, Vav and WASP, play critical roles (16-19). However, WASP and Vav are complex molecules with functions that may or may not require cytoskeletal regulation (20,21). The Rho family GTPases Rac and Cdc42 are the central regulators of cytoskeletal dynamics in many cell types (22). Although it has been established that Rac is required for cell coupling and polarization of cytolytic granules (16), the role Cdc42 has not been addressed. Despite the established importance of ...

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T/B‐cell interactions are more transient in response to weak stimuli in SLE‐prone mice

et al. 2014

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Changes in immune function during the course of systemic lupus erythematosus (SLE) are well characterized. Class-switched antinuclear antibodies are the hallmark of SLE, and T/B- cell interactions are thus critical. However, changes in immune function contributing to disease susceptibility are unknown. Here, we have analyzed primary T and B cells from a mouse model of SLE prior to the onset of disease. To allow cognate T-cell activation with low affinity, we have developed a lower potency peptide ligand for the OTII T-cell receptor. T and B-cell couples formed less frequently and retained their polarity less efficiently preferentially in response to low affinity stimulation in SLE-prone mice. This matched decreased recruitment of actin and Vav1 and an enhanced PKCΘ recruitment to the cellular interface in T cells. The induction of the germinal center B-cell marker GL7 was increased in T/B cell couples from SLE-prone mice when the T-cell numbers were limited. However, the overall gene expression changes were marginal. Taken together, the enhanced cell couple transience may allow a more efficient sampling of a large number of T/B cell couples, preferentially in response to limiting stimuli, therefore enhancing the immune reactivity in the development of SLE.

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Specific Patterns of Cdc42 Activity Are Related to Distinct Elements of T Cell Polarization

Cited by 50 publications

References 37 publications

A Large T Cell Invagination with CD2 Enrichment Resets Receptor Engagement in the Immunological Synapse

A Large T Cell Invagination with CD2 Enrichment Resets Receptor Engagement in the Immunological Synapse

Transience in polarization of cytolytic effectors is required for efficient killing and controlled by Cdc42

T/B‐cell interactions are more transient in response to weak stimuli in SLE‐prone mice

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