Actin Dynamics at the T Cell Synapse as Revealed by Immune-Related Actinopathies

Abstract

The actin cytoskeleton is composed of dynamic filament networks that build adaptable local architectures to sustain nearly all cellular activities in response to a myriad of stimuli. Although the function of numerous players that tune actin remodeling is known, the coordinated molecular orchestration of the actin cytoskeleton to guide cellular decisions is still ill defined. T lymphocytes provide a prototypical example of how a complex program of actin cytoskeleton remodeling sustains the spatio-temporal control of key cellular activities, namely antigen scanning and sensing, as well as polarized delivery of effector molecules, via the immunological synapse. We here review the unique knowledge on actin dynamics at the T lymphocyte synapse gained through the study of primary immunodeficiences caused by mutations in genes encoding actin regulatory proteins. Beyond the specific roles of individual actin remodelers, we further develop the view that these operate in a coordinated manner and are an integral part of multiple signaling pathways in T lymphocytes.

Molecular Tuning of Actin Dynamics in Leukocyte Migration as Revealed by Immune-Related Actinopathies

“…All phases of IS formation are controlled by a complex network of activatory and inhibitory stimuli and require sophisticated orchestration of actin-cytoskeleton [reviewed in (133)]. In accordance, numerous actin-related IEIs have been associated with defects in morphology and functions of IS, such as T cell activation, cytokine secretion and cytolytic activity (reviewed in (14); summarized in Table 1). In addition to T cells, the other subsets of lymphocytes including B cells, NK cells and innate lymphoid cells (ILCs) also assemble IS with partner cells or target cells.…”

“…In addition, we sorted identified defects in motility by the experimental model used in the study: primary material from patient versus cellular and animal models of the specific gene defect. The molecular mechanisms affected in actinopathies span multiple facets of the molecular machinery responsible for actin remodelling, as detailed in ( 14 ). Since multiple molecular layers operate upstream of actin remodelling, it is not obvious to define a threshold for the inclusion of gene defects falling under the umbrella of actinopathies.…”

“…The immunological synapse (IS) describes a tight junction formed by a T cell with either an antigen-presenting cell or an infected cell. At the tissue level formation of IS consists of 4 major phases ( Figures 2-5 A~D ): a) initial contact, b) spreading, c) mature synapse and d) destabilisation and termination [reviewed in ( 14 )]. All phases of IS formation are controlled by a complex network of activatory and inhibitory stimuli and require sophisticated orchestration of actin-cytoskeleton [reviewed in ( 133 )].…”

“…The elucidation of molecular mechanisms underlying IEIs has revealed that more than 20 are either directly caused by, or associated with, defective actin cytoskeleton remodelling (10)(11)(12)(13)(14). These disease entities might therefore be considered as actinopathies specific to the immune system (from here onwards referred to as actinopathies).…”

“…In the context of leukocyte migration, the knowledge we have today about the specific roles of actin regulators stems in part from the study of rare inborn errors of immunity (IEI) caused by mutations in corresponding genes. The elucidation of molecular mechanisms underlying IEIs has revealed that more than 20 are either directly caused by, or associated with, defective actin cytoskeleton remodelling ( 10 – 14 ). These disease entities might therefore be considered as actinopathies specific to the immune system (from here onwards referred to as actinopathies).…”