Clathrin mediates both internalization and vesicular release of triggered T cell receptor at the immunological synapse through distinct adaptors

Abstract

Ligation of the T cell receptor (TCR) to peptide-MHC complexes initiates signaling leading to T cell activation. Regulation of T cell responses also requires mechanisms to stop this signaling and to downregulate surface expression of the receptor. T cells achieve this both by TCR internalization and by releasing TCR loaded vesicles directly from the plasma membrane. How these distinct fates are coordinated is unknown. Here we show that clathrin is recruited to TCR microclusters by HRS and STAM2 and that this process is essential for TCR release. Subsequently, EPN1 recruits clathrin to the remaining antigen conjugated TCRs to enable a late wave of TCR endocytosis. With these results we demonstrate two clathrin-dependent mechanisms and show how the clathrin machinery participates in membrane evagination and invagination depending upon the adaptor recruiting it. These sequential mechanisms mediate bi-directional membrane exchange at the immunological synapse, providing a scaffold for critical communication.

T-cell trans-synaptic vesicles are distinct and carry greater effector content than constitutive extracellular vesicles

“…The requirement for antigen sensing and the integration of multiple juxtacrine signals (i.e., trans-receptor-ligand interactions enabled by the nanometer proximity of the opposing cell membranes) enables a highly regulated and efficient exchange of supramolecular effectors across immunological synapses. In antigen-dependent contacts, T cells efficiently transfer extracellular vesicles containing T-cell antigen receptors (TCR) to APCs as early as 10-30 min of interaction 6,12 . Similarly, CD40 ligand (CD40L), which is essential for B-cell help and the initiation of germinal center reactions 13 , is transferred from T cells to B cells in a contact-, CD40-and antigen-dependent manner 14,15 .…”