Understanding the Structure and Function of the Immunological Synapse

The immunological synapse has been an area of very active scientific interest over the last decade. Surprisingly, much about the synapse remains unknown or is controversial.  Here we review some of these current issues in the field:  how the synapse is defined, its potential role in T-cell function, and our current understanding about how the synapse is formed.T cells are activated when they recognize peptide-MHC complexes on the surface of antigen presenting cells (APC) (Babbitt et al. 1985). But the exact process regarding how antigenic pMHC complexes are recognized and transduced into signals is still incompletely understood. Naïve T cells enter secondary lymphoid organs such as the lymph node and scan dendritic cells for the presence of rare specific pMHC complexes (Miller et al. 2004). After recognizing less than 10 specific pMHC complexes, naïve T cells maintain long contacts (6–18 h) with dendritic cells before being committed to enter cell cycle and differentiate into effector T cells (Iezzi et al. 1998; Irvine et al. 2002; Mempel et al. 2004).The immunological synapse (IS) refers to the organization of membrane proteins that occurs at the interface between the T cell and the APC during these long contacts and also during the effector phase (Grakoui et al. 1999; Monks et al. 1998). Interest in studying the IS stems from ideas that the supramolecular structures that form at the IS underlies the high sensitivity of T cell recognition and that understanding these structures will lead to better insights into how antigen recognition leads to the decision of a T cell to proliferate, differentiate, and function.Springer first put forward the concept that receptors would segregate laterally during cell interactions (Springer 1990). Subsequently, Kupfer was the first to show that proteins in the contact area between a T cell and APC segregate laterally (Monks et al. 1998). Specifically, he noted that the integrin, LFA-1, became concentrated in an outer ring, known as the peripheral supramolecular activation complex (pSMAC) and the TCR became concentrated in the center, in a zone known as the central supramolecular activation complex (cSMAC) (Monks et al. 1998)(Fig. 1). We showed that CD2 could segregate from LFA-1 and concentrate in the center of a hybrid cell-planar bilayer junction and suggested that these patterns and those described by Monks et al. (1998) provided evidence for the previously hypothesized immunological synapse (Dustin et al. 1998; Norcross 1984). The function of this receptor segregation is still not completely understood but it was initially hypothesized that formation of this pattern might be related to T-cell activation and constitute a “molecular machine” that would be formed in response to the presence of antigenic ligand and that this “molecular machine” might function to sustain signaling for long periods of time and direct subsequent T-cell differentiation (Grakoui et al. 1999).Open in a separate windowFigure 1.Structure of the immunological synapse. The basic structure of the “organized” immunological synapse with SMACs is shown (left). In the center is the central supramolecular activation complex or cSMAC, which contains receptors like the TCR, CD28, CD4, CD8, and CD2. Newer studies suggest that the cSMAC may be divided into an outer area containing CD28 and an inner area containing the TCR (not shown). The ring that surrounds the cSMAC is called the peripheral supramolecular activation complex or pSMAC. This domain is mainly populated by the integrin molecule LFA-1. Outside of the pSMAC is another domain known as the distal supramolecular activation complex. Originally the dSMAC was thought not be important and contain all of the molecules that are not specifically recruited to the cSMAC or pSMAC but it is increasingly becoming appreciated that the dSMAC is an area of active membrane movement. This suggests that the pSMAC and dSMAC may be analogous to the actin structures known as the lamellae and lamellipodia, respectively (right).