Actin polymerization-dependent activation of Cas-L promotes immunological synapse stability

Immunol Cell Biol. 2016 Nov;94(10):981-993. doi: 10.1038/icb.2016.61. Epub 2016 Jun 30.

Abstract

The immunological synapse formed between a T-cell and an antigen-presenting cell is important for cell-cell communication during T-cell-mediated immune responses. Immunological synapse formation begins with stimulation of the T-cell receptor (TCR). TCR microclusters are assembled and transported to the center of the immunological synapse in an actin polymerization-dependent process. However, the physical link between TCR and actin remains elusive. Here we show that lymphocyte-specific Crk-associated substrate (Cas-L), a member of a force sensing protein family, is required for transport of TCR microclusters and for establishing synapse stability. We found that Cas-L is phosphorylated at TCR microclusters in an actin polymerization-dependent fashion. Furthermore, Cas-L participates in a positive feedback loop leading to amplification of Ca2+ signaling, inside-out integrin activation, and actomyosin contraction. We propose a new role for Cas-L in T-cell activation as a mechanical transducer linking TCR microclusters to the underlying actin network and coordinating multiple actin-dependent structures in the immunological synapse. Our studies highlight the importance of mechanotransduction processes in T-cell-mediated immune responses.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / metabolism*
  • Animals
  • Calcium / metabolism
  • Cell Adhesion
  • Crk-Associated Substrate Protein / deficiency
  • Crk-Associated Substrate Protein / metabolism*
  • Immunological Synapses / metabolism*
  • Integrins / metabolism
  • Lymphocyte Activation / immunology
  • Mice, Inbred C57BL
  • Models, Immunological
  • Phosphorylation
  • Polymerization*
  • Protein Transport
  • Receptors, Antigen, T-Cell / metabolism
  • T-Lymphocytes / metabolism

Substances

  • Actins
  • Crk-Associated Substrate Protein
  • Integrins
  • Receptors, Antigen, T-Cell
  • Calcium