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

Abstract

Motility is a crucial activity of immune cells allowing them to patrol tissues as they differentiate, sample or exchange information, and execute their effector functions. Although all immune cells are highly migratory, each subset is endowed with very distinct motility patterns in accordance with functional specification. Furthermore individual immune cell subsets adapt their motility behaviour to the surrounding tissue environment. This review focuses on how the generation and adaptation of diversified motility patterns in immune cells is sustained by actin cytoskeleton dynamics. In particular, we review the knowledge gained through the study of inborn errors of immunity (IEI) related to actin defects. Such pathologies are unique models that help us to uncover the contribution of individual actin regulators to the migration of immune cells in the context of their development and function.

Keywords: IEI; actin; actin regulators; cell migration; chemotaxis; cytoskeleton; inborn errors of immunity; leukocytes.

Figure 1

Motility defects in actinopathies at the organism level. (A) Leukocyte trafficking in the bone marrow. (B) T lymphocyte trafficking in the thymus. (C) Recirculation of leukocytes through blood, lymphatic system and lymph nodes. (D) Migration of leukocytes within the skin. (E) Migration of leukocytes within the lungs. Red lines indicate steps of leukocyte trafficking affected by actinopathies with affected genes displayed in corresponding bubble. Lymphatic vessels are depicted in green, while red vessels are depicted in red.

Figure 2

Migratory challenges and actinopathy-associated defects of effector CD8⁺ T cells on the tissue level. (1) Weak adhesion (rolling) of effector T cells after interaction with activated endothelium. (2) Adhesion at the site of exit. (3) Exit of the blood vessel by migration between (3a) or through (3b) endothelium cells. (4) Interstitial navigation following chemokine gradient. (5) Execution of cytolytic activity at the site of infection. (5a) Interaction with target cells. (5b) Kynapse-based scanning of target cells. (5c) Development of IS with infected cells and delivery of cytotoxic compounds. (5d) Destabilization of immune synapse (IS) and detachment from targeted cell. (6) Compromised attachment of WASP-deficient T cells to the endothelium at the exit site. (7) Reduced capacity of directional migration in tissue environment of HEM1-deficient T cells. (8) Cytothripsis of DOCK8-deficient T cells during migration through confined environment. (9) Impaired formation of IS by WASP-deficient T cells.

Figure 3

Actin-based protrusions affected in actinopathies on the ultrastructural level. (A) Migrating lymphocyte with uropod, filopodia and lamellipodium. (B) Adhering DC emitting an array of podosomes. (C) Circulating neutrophil decorated with microvilli. Red arrows indicate direction of movement. Protein names listed in red indicate their involvement in the corresponding protrusions.