Nuclear morphology and chromatin compaction modulate T cell cytoskeletal remodeling and immune synapse formation.

T cell activation induces a rapid reorganization of the actin cytoskeleton, facilitating cell spreading on antigen-presenting cells (APCs). As the nucleus, the cell's largest organelle, constrains cell shape changes, its mechanical properties, governed by chromatin compaction and heterochromatin density, are likely to play a critical role in T cell spreading and activation. However, the contribution of nuclear mechanics to T cell activation remains elusive. Here, we demonstrate that T cell spreading is accompanied by nuclear deformation and increased chromatin compaction. Reducing chromatin compaction, which is known to soften the nucleus, enhances cell spread area and nuclear deformation but decreases F-actin accumulation and peripheral enrichment at the immune synapse. Conversely, enhancing chromatin compaction restricts spreading and deformation but promotes peripheral F-actin organization. This reveals a reciprocal relationship between chromatin compaction and cytoskeletal organization. We identify SUN proteins and myosin as key mediators through which chromatin compaction modulates actin morphology and cell shape, enabling T cells to adapt to antigen-presenting surfaces of varying stiffness. These findings underscore the pivotal role of chromatin compaction in T cell activation, highlighting the mechanical interplay between the nucleus and cytoskeleton, and suggesting novel insights into T cell mechano-responsiveness.