The immunological synapse is built on a foundation of cell adhesion molecules (CAMs) that I studied as a graduate student in the lab of Timothy Springer at Harvard Medical School.  The Springer lab had generated monoclonal antibodies that inhibit killing function of cytotoxic T lymphocytes (CTL) and defined short CAM pairs (15 nm) and long CAM pairs (~30 nm) with thousands of these interactions bridging the synapse.  I did work defining components of the long CAMs referred to as intercellular adhesion molecules (ICAMs).  I also discovered that the activity of the long CAM on T cells was determined by the TCR- providing the missing link between antigen specificity and the bridge building activity of the adhesion molecules.

The existence of long and short CAMs raised the possibility that the immunological synapse would have multiple “levels” of 15 nm and 30 nm spacing between membranes.  We demonstrated segregation of the long short and long CAMs in a model synapse, which was complementary to results from Kupfer demonstrating a bull’s eye immune synapse with TCR in the center surrounded by a ring of long CAMs.  Higher resolution imaging later revealed that these supramolecular activation clusters (SMACs) were mosaics of smaller elements- such that thousands of receptors were organized into tens of microclusters that coalesced into radially symmetric SMACs.  TCR signaling is concentrated in microclusters that form in the periphery of the immunological synapse.

Recently, we have discovered that these TCR microclusters are transported to the center of the synapse where these membrane domains bud to form extracellular vesicles that are directly handed off to the antigen-presenting cell.  We refer to these as synaptic ectosomes.  We are currently investigating the potential of synaptic ectosomes as a novel mechanism for information transfer in the immunological synapse, particularly in the context of T cell help for high affinity antibody production.

The current picture of the immunological synapse combines the multilevel interface, directed secretion and trans-synaptic vesicle release.  Key therapeutics such as anti-CTLA-4 and anti-PD-1 are known to modulate immunological synapses for cancer therapy.  Future studies will focus on building a platform to systematically screen for immunological synapse modulators with therapeutic applications“. [Michael L. Dustin]