ABSTRACT
Activation of naive T cells by antigen-presenting cells (APCs) is an essential step in mounting an adaptive immune response. It is known that antigen recognition and T cell receptor (TCR) signaling depend on forces applied by the T cell actin cytoskeleton, but until recently, the underlying mechanisms have been poorly defined. Here, we review recent advances in the field, which show that specific actin-dependent structures contribute to the process in distinct ways. In essence, T cell priming involves a tug-of-war between the cytoskeletons of the T cell and the APC, where the actin cytoskeleton serves as a mechanical intermediate that integrates force-dependent signals. We consider each of the relevant actin-rich T cell structures separately and address how they work together at the topologically and temporally complex cell-cell interface. In addition, we address how this mechanobiology can be incorporated into canonical immunological models to improve how these models explain T cell sensitivity and antigenic specificity.
Subject(s)
Actin Cytoskeleton/genetics , Actins/genetics , Antigen-Presenting Cells/immunology , Immunological Synapses/genetics , Mechanotransduction, Cellular , Actin Cytoskeleton/immunology , Actins/immunology , Adaptive Immunity/immunology , Cell Communication/immunology , Cytoskeleton/genetics , Cytoskeleton/immunology , Humans , Immunological Synapses/immunology , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Models, Immunological , Pseudopodia/immunology , Pseudopodia/ultrastructure , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Signal Transduction/genetics , T-Lymphocytes/immunologyABSTRACT
B lymphocytes capture antigens from the surface of presenting cells by forming an immune synapse. Local secretion of lysosomes, which are guided to the synaptic membrane by centrosome repositioning, can facilitate the extraction of immobilized antigens. However, the molecular basis underlying their delivery to precise domains of the plasma membrane remains elusive. Here we show that microtubule stabilization, triggered by engagement of the B cell receptor, acts as a cue to release centrosome-associated Exo70, which is redistributed to the immune synapse. This process is coupled to the recruitment and activation of GEF-H1, which is required for assembly of the exocyst complex, used to promote tethering and fusion of lysosomes at the immune synapse. B cells silenced for GEF-H1 or Exo70 display defective lysosome secretion, which results in impaired antigen extraction and presentation. Thus, centrosome repositioning coupled to changes in microtubule stability orchestrates the spatial-temporal distribution of the exocyst complex to promote polarized lysosome secretion at the immune synapse.