The synapse and cytolytic machinery of cytotoxic T cells

Abstract

Cytotoxic T lymphocytes (CTLs) rapidly kill target cells via the release of lytic granules into the immunological synapse, a process directed by the docking of the centrosome at the plasma membrane. New evidence highlights how signal strength and avidity influence the recruitment of cytolytic machinery to the synapse, and the role of each synaptic compartment. Release of cytolytic effector proteins, including perforin and FasL, is controlled at multiple levels and is also influenced by the avidity of the interaction. New imaging technologies and the use of photoactivatable peptides have allowed the dissection of signalling molecules involved in each step of the cytolytic process. This review highlights the important role of avidity in controlling how a T cell kills its target.

Figure 1. The immunological synapse: a highly organised interface.

The interface between CTL and target is organised with an adhesion ring: the peripheral supramolecular activation complex (pSMAC) with leucocyte function associated antigen 1 (LFA-1) on the CTL and intercellular adhesion molecule (ICAM) on the target cell. Within the pSMAC is the central SMAC, where TCR accumulates, and beside it the secretion domain where lytic granules fuse to release their content. The centrioles of the centrosome dock beside the cSMAC, which acts as a focal point for minus end microtubule-mediated delivery of lytic granules. Actin accumulation occurs in a distal SMAC (dSMAC).

Figure 2. Mechanism of lytic granule release.

Recognition of the target MHC class I molecules bound to peptide antigen occurs via the TCR. Once the TCR is engaged, the most proximal signalling molecule to be recruited is Lck (shown in green). The centrosome (γ-tubulin, yellow), which is normally perinuclear, polarises towards the synapse and docks at the plasma membrane. The granules (LAMP-1, red) migrate towards the centrosome, where they dock and fuse with at the plasma membrane, releasing their contents into the synaptic cleft, causing target cell destruction.