T cells: Lamin A links synapse to nucleus

  • Lucy Bird
  • Published 2014 in Nature Reviews Immunology

Abstract

reorganization of the structural and signalling components of the cell at the site of contact with an antigenpresenting cell (APC) to form the immunological synapse. According to a new study, this reorganization and the ensuing T cell activation is supported by the nuclear envelope intermediate filaments A-type lamins, which physically link the nucleoskeleton, the cytoskeleton and the plasma membrane. First, the authors observed a marked but transient increase in the amount of A-type lamins (lamin A and lamin C) in T cells following activation through the T cell receptor (TCR). This increase occurred rapidly after T cell exposure to antigenloaded APCs but not after exposure to APCs without antigen. Moreover, compared with wild-type mouse splenocytes, splenocytes that were deficient in A-type lamins (Lmna–/–) showed a reduction in cell surface expression of activation markers (such as CD25 and CD69) following TCR stimulation. Next, the authors tested whether A-type lamins enhance T cell activation by influencing the formation of the immunological synapse. Indeed, time-lapse confocal microscopy revealed that T cells expressing A-type lamins formed more contacts with antigenloaded APCs than did T cells that lacked A-type lamins, and these inter actions lasted longer in the presence of A-type lamins. In addition, tracking the dynamics of fluorescently labelled CD3ζ molecules following T cell stimulation showed that more CD3-containing microclusters formed in the central region of the contact area and disappeared from view faster in T cells that expressed A-type lamins than in A-type lamin-deficient cells, which suggests a role for A-type lamins in CD3 internalization. Notably, following TCR stimulation, the microtubule-organizing centre translocated faster to the immunological synapse and F-actin poly merization was increased in A-type lamin-expressing T cells compared with control cells. In line with this role for A-type lamins in enhanced synapse formation, the phosphorylation of signalling components downstream of TCR stimulation (such as VAV1, myosin IIA and extracellular signalregulated kinase 1) was also increased by the presence of A-type lamins. So, how does a protein that is confined to the nucleus regulate synapse formation? The authors show that A-type lamins mediate these effects by physically connecting proteins of the linker of nucleoskeleton and cytoskeleton (LINC) complex, nesprins (which are located in the outer nuclear membrane and connect with cytoplasmic microtubules, actin and intermediate filaments) and SUN (which interacts with lamin A in the perinuclear space and links to nesprins). Accordingly, overexpression of dominant-negative forms of nesprins and SUN abrogated the effect of A-type lamins on synapse formation. These data show that A-type lamins promote synapse formation and T cell activation by connecting the nuclear lamina with the cytoskeleton through the LINC complex proteins. Lucy Bird T C E L L S

DOI: 10.1038/nri3692

Cite this paper

@article{Bird2014TCL, title={T cells: Lamin A links synapse to nucleus}, author={Lucy Bird}, journal={Nature Reviews Immunology}, year={2014}, volume={14}, pages={356-357} }