Nuclear Envelope Lamin-A Couples Actin Dynamics with Immunological Synapse Architecture and T Cell Activation

Communication between the nuclear lamina protein lamin-A and the actin cytoskeleton is required for optimal T cell responses. Nuclear Support for T Cell Activation A-type lamins are filamentous proteins that form the nuclear lamina inside the inner nuclear membrane. As well as maintaining the mechanical integrity of the nucleus, A-type lamins physically connect the nucleus and the actin cytoskeleton by associating with the linker of nucleoskeleton and cytoskeleton (LINC) complex. González-Granado et al. found that the abundance of lamin-A was rapidly and transiently increased in mouse and human CD4+ T cells in response to stimulation of the T cell receptor. Lamin-A enhanced F-actin polymerization at the immunological synapse between the T cells and antigen-presenting cells, thereby boosting T cell activation. Disruption of the interaction between lamin-A and the LINC complex also decreased T cell activation in culture, and mice lacking lamin-A in immune cells exhibited reduced T cell activation in response to antigen. These results suggest that the nuclear skeleton communicates with the cytoskeleton to enable optimal T cell activation. In many cell types, nuclear A-type lamins regulate multiple cellular functions, including higher-order genome organization, DNA replication and repair, gene transcription, and signal transduction; however, their role in specialized immune cells remains largely unexplored. We showed that the abundance of A-type lamins was almost negligible in resting naïve T lymphocytes, but was increased upon activation of the T cell receptor (TCR). The increase in lamin-A was an early event that accelerated formation of the immunological synapse between T cells and antigen-presenting cells. Polymerization of F-actin in T cells is a critical step for immunological synapse formation, and lamin-A interacted with the linker of nucleoskeleton and cytoskeleton (LINC) complex to promote F-actin polymerization. We also showed that lamin-A expression accelerated TCR clustering and led to enhanced downstream signaling, including extracellular signal–regulated kinase 1/2 (ERK1/2) signaling, as well as increased target gene expression. Pharmacological inhibition of the ERK pathway reduced lamin-A–dependent T cell activation. Moreover, mice lacking lamin-A in immune cells exhibited impaired T cell responses in vivo. These findings underscore the importance of A-type lamins for TCR activation and identify lamin-A as a previously unappreciated regulator of the immune response.