The immunological synapse

Abstract

T-cell activation requires interaction of T-cell antigen receptors with proteins of the major histocompatibility complex (antigen). This interaction takes place in a specialized cell-cell junction referred to as an immunological synapse. The immunological synapse contains at least two functional domains: a central cluster of engaged antigen receptors and a surrounding ring of adhesion molecules. The segregation of the T-cell antigen receptor (TCR) and adhesion molecules is based on size, with the TCR interaction spanning 15 nm and the lymphocyte-function-associated antigen-1 (LFA-1) interaction spanning 30-40 nm between the two cells. Therefore, the synapse is not an empty gap, but a space populated by both adhesion and signaling molecules. This chapter considers four aspects of the immunological synapse: the role of migration and stop signals, the role of the cytoskeleton, the role of self-antigenic complexes, and the role of second signals.

Figure 1

The development of the immunological synapse. Images adapted from [2] based on fluorescence microscope images of T-cell interaction with agonist MHC–peptide complexes (green) and ICAM-1 (red) in a supported planar bilayer with a T cell. The accumulation of fluorescence represents interactions in different time frames. (a) Within seconds, the T cell attaches to the substrate using LFA-1/ICAM-1 interactions in the center based on TCR signaling triggered at the periphery of the contact area. (b) Over a period of minutes, the engaged TCRs are translocated to the center of the contact area. (c) The final pattern, with a central cluster of engaged TCRs surrounded by a ring of engaged LFA-1, is stable for hours. Molecular markers for the cSMAC and pSMAC are indicated. For scale, the pSMAC is ~5 μm across. ADAP, adhesion and degranulation adapter protein; cSMAC, central supramolecular activation cluster; ICAM, intercellular adhesion molecule; LFA, lymphocyte-function-associated antigen; MHCp, major histocompatibility complex protein complexed to a foreign or self-peptide; PKC-θ, a protein kinase C isoform that is activated by DAG but not Ca²⁺; pSMAC, peripheral supramolecular activation cluster – the ring of LFA-1 and talin on the T cell and ICAM-1 on the antigen-presenting cell in the mature immunological synapse; TCR, T-cell antigen receptor.