Seminars in Immunology 15 (2003) 317–324 The protean immune cell synapse: a supramolecular structure with many functions Daniel M. Davis a,∗ , Tadahiko Igakura b , Fiona E. McCann a , Leo M. Carlin a , Katja Andersson c , Bruno Vanherberghen a,c , Anna Sjöström c , Charles R.M. Bangham b , Petter Höglund c a Department of Biological Sciences, Sir Alexander Fleming Building, Imperial College London, South Kensington Campus, London SW7 2AZ, UK b Department of Immunology, Wright-Fleming Institute, Imperial College London, St Mary’s Campus, London W2 1PG, UK c Microbiology and Tumor Biology Center, Karolinska Institutet, Box 280, Stockholm S-171 77, Sweden Abstract Heterogeneity in the supramolecular organization of immunological synapses arises from the involvement of different cells, distinct environmental stimuli, and varying levels of protein expression. There may also be heterogeneity in the types and amounts of cell surface proteins and lipids that transfer between lymphocytes during immune surveillance. In addition, immune cells can be involved in the assembly of a ‘viral synapse’, such that micrometer-scale organization of proteins at intercellular contacts occurs during transmission of a virus between T cells. Thus, while there may be unity in molecular mechanisms underlying the organization of cell surface receptors at immune cell synapses, there is diversity in their function. © 2003 Elsevier Ltd. All rights reserved. Keywords: Cellular activation; Immunological synapse; Viral synapse; Natural Killer cells; T lymphocytes 1. Introduction Intriguingly, the number of predicted protein architectures devoted to extracellular or transmembrane communication appears to be significantly greater in the human genome than in worms and flies, far more than the increase in intracel- lular protein architectures (Fig. 40 in Ref. [1]). Thus, com- plexity has evolved in the human proteome to serve inter- cellular, more than intracellular, communication. Recently, imaging the intercellular communication between murine or human lymphocytes revealed an unexpected level of com- plexity. Proteins segregate into micrometer-scale domains, i.e. supramolecular activation clusters (SMAC), across the intercellular contact, creating an immune or immunologi- cal synapse (IS) [2–7]. Lymphocyte surface receptors such as T cell receptor (TCR), B cell receptor (BCR) or in- Abbreviations: SMAC, supramolecular activation cluster; IS, im- mune or immunological synapse; VS, viral or virological synapse; LSCM, laser scanning confocal microscopy; HTLV-1, human T lym- photropic virus Type 1; MTOC, microtubule organizing center; KIR, Killer immunoglobulin-like receptor; TCR, T cell receptor; BCR, B cell receptor; CTL, cytotoxic T lymphocytes; MHC, major histocompatibility complex; HLA, human leukocyte antigen; GFP, green fluorescent protein ∗ Corresponding author. Tel.: +44-20-7594-5420; fax: +44-20-7594-3044. E-mail address: d.davis@imperial.ac.uk (D.M. Davis). hibitory Killer immunoglobulin-like receptor (KIR), adap- tor proteins such as CD2 associated protein (CD2AP), cy- toskeletal linkers such as talin and ezrin, and downstream signaling molecules such as PKC have all been shown to organize at an IS. Also, major histocompatibility complex (MHC) proteins, integrins and several other cell surface pro- teins transfer between lymphocytes during immune surveil- lance [8]. Here, we discuss the possible functions of the IS and the intercellular transfer of cell surface proteins during immune surveillance. Also, we discuss the recent observa- tion that the retrovirus human T lymphotropic virus Type 1 (HTLV-1) appears to exploit a supramolecular organization of proteins similar to that seen at the IS to facilitate trans- mission between T cells. 2. Heterogeneity in the function of the IS Recent images lucidly demonstrate that the principal func- tion of T cell surveillance is to search for as few as 1–10 agonist peptides amongst the many thousands presented by MHC proteins [9]. In contrast, Natural Killer (NK) cell cy- totoxicity is controlled by a balance between activating and inhibitory signals triggered by recognition of relatively large numbers of invariant epitopes [10–12]. Yet despite these dif- ferent strategies for immune surveillance, both T and NK 1044-5323/$ – see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.smim.2003.09.005