Faculty Opinions recommendation of Dendritic cell actin dynamics control contact duration and priming efficiency at the immunological synapse.

ABSTRACT T-cell activation by antigen-presenting cells is accompanied by actin polymerization, T-cell receptor (TCR) capping, and formation of the immunological synapse. However, whether actin-dependent events are required for T-cell function is poorly understood. Herein, we provide evidence for an unexpected negative regulatory role of the actin cytoskeleton on TCR-induced cytokine production. Disruption of actin polymerization resulted in prolonged intracellular calcium elevation in response to anti-CD3, thapsigargin, or phorbol myristate acetate plus ionomycin, leading to persistent NFAT (nuclear factor of activated T cells) nuclear duration. These events were dominant, as the net effect of actin blockade was augmented interleukin 2 promoter activity. Increased surface expression of the plasma membrane Ca2+ ATPase was observed upon stimulation, which was inhibited by cytochalasin D, suggesting that actin polymerization contributes to calcium export. Our results imply a novel role for the actin cytoskeleton in modulating the duration of Ca2+-NFAT signaling and indicate that actin dynamics regulate features of T-cell activation downstream of receptor clustering.

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Actin dynamics at the immunological synapse

Cell Health and Cytoskeleton ◽

10.2147/chc.s9960 ◽

2010 ◽

pp. 33

Author(s):

Francisco Francisco Sanchez-Madrid

Keyword(s):

Immunological Synapse ◽

Actin Dynamics

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Cutting Edge: The Dendritic Cell Cytoskeleton Is Critical for the Formation of the Immunological Synapse

The Journal of Immunology ◽

10.4049/jimmunol.166.3.1452 ◽

2001 ◽

Vol 166 (3) ◽

pp. 1452-1456 ◽

Cited By ~ 161

Author(s):

Monther M. Al-Alwan ◽

Geoffrey Rowden ◽

Timothy D. G. Lee ◽

Kenneth A. West

Keyword(s):

Dendritic Cell ◽

Immunological Synapse ◽

Cutting Edge ◽

Cell Cytoskeleton

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Dendritic cell-expressed common gamma-chain recruits IL-15 for trans-presentation at the murine immunological synapse

Wellcome Open Research ◽

10.12688/wellcomeopenres.14493.1 ◽

2018 ◽

Vol 3 ◽

pp. 84 ◽

Cited By ~ 1

Author(s):

Chiara Beilin ◽

Kaushik Choudhuri ◽

Gerben Bouma ◽

Dessislava Malinova ◽

Jaime Llodra ◽

...

Keyword(s):

T Cell ◽

Dendritic Cell ◽

T Cell Activation ◽

Cell Activation ◽

Immunological Synapse ◽

Nk Cell ◽

Severe Combined Immunodeficiency ◽

Cd4 T Cell ◽

Gamma Chain

Background:Mutations of the common cytokine receptor gamma chain (γc) cause Severe Combined Immunodeficiency characterized by absent T and NK cell development. Although stem cell therapy restores these lineages, residual immune defects are observed that may result from selective persistence of γc-deficiency in myeloid lineages. However, little is known about the contribution of myeloid-expressed γc to protective immune responses. Here we examine the importance of γc for myeloid dendritic cell (DC) function.Methods:We utilize a combination ofin vitroDC/T-cell co-culture assays and a novel lipid bilayer system mimicking the T cell surface to delineate the role of DC-expressed γc during DC/T-cell interaction.Results:We observed that γc in DC was recruited to the contact interface following MHCII ligation, and promoted IL-15Rα colocalization with engaged MHCII. Unexpectedly, trans-presentation of IL-15 was required for optimal CD4+T cell activation by DC and depended on DC γc expression. Neither recruitment of IL-15Rα nor IL-15 trans-signaling at the DC immune synapse (IS), required γc signaling in DC, suggesting that γc facilitates IL-15 transpresentation through induced intermolecularcisassociations or cytoskeletal reorganization following MHCII ligation.Conclusions:These findings show that DC-expressed γc is required for effective antigen-induced CD4+ T cell activation. We reveal a novel mechanism for recruitment of DC IL-15/IL-15Rα complexes to the IS, leading to CD4+ T cell costimulation through localized IL-15 transpresentation that is coordinated with antigen-recognition.

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Actin Dynamics Regulates Dendritic Cell-Mediated Transfer of HIV-1 to T Cells

Cell ◽

10.1016/j.cell.2015.12.036 ◽

2016 ◽

Vol 164 (4) ◽

pp. 695-709 ◽

Cited By ~ 54

Author(s):

Mickaël M. Ménager ◽

Dan R. Littman

Keyword(s):

T Cells ◽

Dendritic Cell ◽

Actin Dynamics ◽

Hiv 1

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Lipid rafts and regulation of the cytoskeleton during T cell activation

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2005.1704 ◽

2005 ◽

Vol 360 (1461) ◽

pp. 1663-1672 ◽

Cited By ~ 31

Author(s):

Karina F Meiri

Keyword(s):

T Cell ◽

Lipid Rafts ◽

T Cell Activation ◽

Cell Activation ◽

Immunological Synapse ◽

Membrane Lipids ◽

Actin Dynamics ◽

Associated Proteins ◽

Liquid Ordered

The ability of polarized cells to initiate and sustain directional responses to extracellular signals is critically dependent on direct communication between spatially organized signalling modules in the membrane and the underlying cytoskeleton. Pioneering work in T cells has shown that the assembly of signalling modules critically depends on the functional compartmentalization of membrane lipids into ordered microdomains or lipid rafts. The significance of rafts in T cell activation lies not only in their ability to recruit the signalling partners that eventually assemble into a mature immunological synapse but also in their ability to regulate actin dynamics and recruit cytoskeletal associated proteins, thereby achieving the structural polarization underlying stability of the synapse—a critical prerequisite for activation to be sustained. Lipid rafts vary quite considerably in size and visualizing the smallest of them in vivo has been challenging. Nonetheless it is now been shown quite convincingly that a surprisingly large proportion—in the order of 50%—of external membrane lipids (chiefly cholesterol and glycosphingolipids) can be dynamically localized in these liquid ordered rafts. Complementary inner leaflet rafts are less well characterized, but contain phosphoinositides as an important functional component that is crucial for regulating the behaviour of the actin cytoskeleton. This paper provides an overview of the interdependency between signalling and cytoskeletal polarization, and in particular considers how regulation of the cytoskeleton plays a crucial role in the consolidation of rafts and their stabilization into the immunological synapse.

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