Immunological synapse derived ectosomes in T cell effector function

This new project will allow us to address fundamental gaps in our understanding of the immunological synapse, a form of communication between between T cells and B cells that is necessary to mount an immune response.

Our innovative and ground-breaking programme aims to determine the role and composition of synaptic ectosomes, particular structures related to immunological synapses, as well as identify ways to manipulate their formation.

We will be using a number of state of the art technologies, including mass spectrometry, deep sequencing, functional assays, single particle imaging, and in vivo microscopy.

SCIENTIFIC CONTEXT

The immunological synapse is a highly conserved scaffold for communication between immune cells built around cooperation of antigen and adhesion receptors. It often takes the form of a bull's eye with a central cluster of antigen receptors surrounded by a ring of adhesion molecules.

We have recently observed that antigen receptor coated extracellular microvesicles bud directly from the center of the immunological synapse - which we define as synaptic ectosomes.

Synaptic ectosomes are transferred to the antigen-presenting cell and can generate signals after the T cell-APC synapse has dissolved.

The hypothesis underlying our programme are 1. that T cells use synaptic ectosomes to communicate with other cells and 2.that this function is congruent with the biological paradigms for a given cell type.

The advantage of this mode of communication is that it may operate on a time frame longer than the relatively short-lived immunological synapse. While neural synapses may last a lifetime, the immunological synapse is a provisional structure that lasts for minutes to hours. Thus, the synaptic ectosomes may deliver more durable instructions that last from days to weeks and continue to influence the responding cells long after the synaptic interaction has dissociated.

Understanding the role of synaptic ectosomes in T cell effector function will require the ability to achieve 3 main objectives:

1. Isolate and characterise the synaptic ectosomes from helper, cytotoxic and regulatory T cells.
2. Test the vesicles for functional effects on B cells, target cells or dendritic cells. 
3. Use gene targeted mice to manipulate synaptic ectosome formation and exosome release by T cells in vivo.

This research will be the first to isolate and study synaptic ectosomes, which have previously not been available for analysis due to their efficient transfer from T cells to antigen presenting cells.