Clathrin controls bidirectional communication between T cells and antigen presenting cells

In circulation, T cells are spherical with selectin enriched dynamic microvilli protruding from the surface. Following extravasation, these microvilli serve another role, continuously surveying their environment for antigen in the form of peptide-MHC (pMHC) expressed on the surface of antigen presenting cells (APCs). Upon recognition of their cognate pMHC, the microvilli are initially stabilized and then flatten into F-actin dependent microclusters as the T cell spreads over the APC. Within 1-5 min, clathrin is recruited by the ESCRT-0 component Hrs to mediate release of T cell receptor (TCR) loaded vesicles directly from the plasma membrane by clathrin and ESCRT-mediated ectocytosis (CEME). After 5-10 min, Hrs is displaced by the endocytic clathrin adaptor epsin-1 to induce clathrin-mediated trans-endocytosis (CMTE) of TCR-pMHC conjugates. Here we discuss some of the functional properties of the clathrin machinery which enables it to control these topologically opposite modes of membrane transfer at the immunological synapse, and how this might be regulated during T cell activation. This graphical abstract depicts a T cell (green) getting activated on an antigen presenting cell (APC, grey). During activation, the T cell initially releases T cell receptor loaded vesicles onto the APC by clathrin and ESCRT-mediated ectocytosis (CEME) before it subsequently internalizes antigen in the form of peptide-MHC from the APC by clathrin-mediated trans-endocytosis (CMTE). In this review we discuss the functional properties of the clathrin machinery which enables it to control these topologically opposite processes. image