Abstract
The immunological synapse is a highly structured and molecularly dynamic interface between communicating immune cells. Although the immunological synapse promotes T cell activation by dendritic cells, the specific organization of the immunological synapse on the dendritic cell side in response to T cell engagement is largely unknown. In this study, confocal and electron microscopy techniques were used to investigate the role of dendritic cell actin regulation in immunological synapse formation, stabilization, and function. In the dendritic cell-restricted absence of the Wiskott-Aldrich syndrome protein, an important regulator of the actin cytoskeleton in hematopoietic cells, the immunological synapse contact with T cells occupied a significantly reduced surface area. At a molecular level, the actin network localized to the immunological synapse exhibited reduced stability, in particular, of the actin-related protein-2/3-dependent, short-filament network. This was associated with decreased polarization of dendritic cell-associated ICAM-1 and MHC class II, which was partially dependent on Wiskott-Aldrich syndrome protein phosphorylation. With the use of supported planar lipid bilayers incorporating anti-ICAM-1 and anti-MHC class II antibodies, the dendritic cell actin cytoskeleton organized into recognizable synaptic structures but interestingly, formed Wiskott-Aldrich syndrome protein-dependent podosomes within this area. These findings demonstrate that intrinsic dendritic cell cytoskeletal remodeling is a key regulatory component of normal immunological synapse formation, likely through consolidation of adhesive interaction and modulation of immunological synapse stability.
Highlights
A crucial step for successful T cell activation is conjugated interaction at the IS, an organized contact interface thought to allow optimal antigen recognition and signal transduction
In the context of DC–T cell IS formation, whereas the role of the T cell cytoskeleton has been well described, few studies have explored the importance of the DC as an active rather than passive participant [5, 6, 58]
Dysregulated actin polymerization or a reduced total F-actin network may make DCs less responsive to external physical cues and less able to form precise structures by transporting or stabilizing transmembrane proteins. This appears to be the case radial symmetry, as a percentage of cells interacting with the a-MHC II bilayer
Summary
A crucial step for successful T cell activation is conjugated interaction at the IS, an organized contact interface thought to allow optimal antigen recognition and signal transduction. IS formation requires the dynamic remodeling of the actin cytoskeleton to distribute membrane areas spatially with distinct protein compositions. Many of the cytoskeletal regulators are conserved between cell types, their precise interactions, effectors, and functions may differ. Little is known about the role of the DC cytoskeleton in active regulation of IS formation, there is some evidence for the involvement of cytoskeletal remodeling and the activity of Rho family GTPases Rac and Rac2 [5,6,7]. The DC actin cytoskeleton has been shown to play a role in CD8 T cell activation [8], and most recently, investigation into DC actin’s effects on transmembrane protein mobility has shown that it promotes T cell adhesion [9]
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