A Dock8-dependent mechanosensitive central actin pool maintains T cell shape and protects the nucleus during...

Area of Science:

• Immunology
• Cell Biology
• Biophysics

Background:

• Immune cells require extensive cellular deformation for migration through complex tissues.
• Loss-of-function mutations in dedicator of cytokinesis 8 (Dock8) cause immunodeficiency due to impaired immune cell migration in dense environments.
• The specific cytoskeletal defects in Dock8-deficient T cells remain unclear.

Purpose of the Study:

• To investigate the specific cytoskeletal defect in Dock8-deficient activated T cells.
• To identify the molecular mechanisms underlying T cell migration in confined environments.
• To understand the consequences of impaired T cell migration on cellular integrity and survival.

Main Methods:

• Comparative analysis of F-actin distribution in wild-type and Dock8-deficient murine and human T cells.
• Investigation of the mechanoresponsive nature of the central actin pool.
• Identification of key proteins involved in the mechanosensitive pathway using genetic and biochemical approaches.

Main Results:

• A central F-actin pool, crucial for T cell shape integrity, was identified in wild-type T cells but absent in Dock8 knockout T cells.
• The central actin pool is mechanoresponsive, appearing only under conditions of high cellular confinement.
• Mammalian sterile 20-like 1 (Mst1) was identified as a key component, alongside Dock8, in this mechanosensitive pathway.
• Loss of the central actin pool led to increased nuclear deformation, DNA damage accumulation, and premature T cell senescence.

Conclusions:

• Dock8 and Mst1 are essential for maintaining T cell shape integrity and survival during migration through confined tissue architectures via a central actin pool.
• The absence of this central actin pool in Dock8-deficient T cells results in significant cellular damage and senescence, contributing to immunodeficiency.
• This study reveals a novel mechanosensitive pathway critical for immune cell function in complex biological environments.