When the TCR complex recognizes MHC-associated peptides on an APC, several T-cell surface proteins and intracellular signaling molecules are rapidly mobilized to the site of T cell APC contact (Fig. 1). This region of physical contact between the T cell and the APC forms a bull's eye–like structure that is called an immune synapse or a supramolecular activation cluster (SMAC). The T-cell molecules that move to the center of the synapse include the TCR complex (the TCR, CD3, and ζ chains), CD4 or CD8 coreceptors, receptors for costimulators (such as CD28), enzymes such as PKCθ, and adaptor proteins that associate with the cytoplasmic tails of the transmembrane receptors. At this region of the synapse, called the c-SMAC (for central SMAC), the distance between plasma membranes of the T cell and the APC is about 15 nm. Integrins remain at the periphery of the synapse, where they function to stabilize the binding of the T cell to the APC, forming the peripheral portion of the SMAC, called the p-SMAC. In this outer part of the synapse, the two membranes are about 40 nm apart. Many signaling molecules found in synapses are initially localized to regions of the plasma membrane that have a lipid content different from the rest of the cell membrane and are called lipid rafts or glycolipid-enriched microdomains. TCR and costimulatory receptor signaling is initiated in these rafts and signaling initiates cytoskeletal rearrangements that allow rafts to coalesce and form the immune synapse.
Fig1. The immune synapse. (A) This figure shows two views of the immunologic synapse in a T cell–APC conjugate (shown as a Nomarski image in panel c). Talin, a protein that associates with the cytoplasmic tail of the leukocyte function-associated antigen 1 (LFA-1) integrin, was revealed by an antibody labeled with a green fluorescent dye, and protein kinase C theta (PKCθ), which associates with the TCR complex, was visualized by antibodies conjugated to a red fluorescent dye. In panels a and b, a two-dimensional optical section of the cell contact site along the x-y axis is shown, revealing the central location of PKCθ and the peripheral location of talin, both in the T cell. In panels d to f, a three-dimensional view of the entire region of cell-cell contact along the x-z axis is provided. Note, again, the central location of PKCθ and the peripheral accumulation of talin. (B) A schematic view of the synapse, showing talin and LFA-1 in the peripheral supramolecular activation cluster (SMAC) (green) and PKCθ and the TCR in the central SMAC (red). ICAM-1, Intercellular adhesion molecule 1; MHC, major histocompatibility complex. (A, From Monks CRF, Freiburg BA, Kupfer H, Sciaky N, Kupfer A. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature. 1998;395:82–86.)
Immune synapses serve several functions during and after T-cell activation. • The synapse forms a stable contact between an antigen-specific T cell and an APC displaying that antigen and becomes the site for assembly of the signaling machinery of the T cell, including the TCR complex, coreceptors, costimulatory receptors, and adaptors. Although some TCR signal trans duction is initiated before the formation of the synapse and is, in fact, required for synapse formation, the immune syn apse itself provides a unique interface for TCR triggering. T-cell activation needs to overcome the problems of a generally low affinity of TCRs for peptide-MHC ligands and the presence of few MHC molecules displaying any one peptide on an APC. The synapse represents a site at which repeated engagement of TCRs can be sustained by this small number of peptide-MHC complexes on the APC, thus facilitating prolonged and effective T-cell signaling.
• The synapse ensures the specific delivery of molecules from a T cell to other cells that are in contact with the T cell. For example, vectorial delivery of secretory granules containing perforin and granzymes from CTLs to target cells occurs at the synapse, allowing for specific killing of the target cell but not bystander cells. Similarly, CD40L-CD40 interactions are facilitated by the accumulation of these molecules on the T cell and APC interfaces of the immune syn apse. Some cytokines are also secreted in a directed manner into the synaptic cleft, from where they are preferentially delivered to the APC that is displaying antigen to the T lymphocyte. This ensures that cytokines act on cells bearing foreign (e.g., microbial) antigens, which are the cells that need to be activated or killed to eliminate these antigens.
• The synapse, especially the c-SMAC region, may also be an important site for the turnover of signaling molecules, primarily by ubiquitination and delivery to late endosomes and lysosomes, where they are enzymatically digested. This degradation of signaling proteins contributes to the termination of T-cell activation and is discussed later.
