Seminars in Immunology 19 (2007) 255–261 Review Molecular mechanisms involved in T cell receptor triggering Kaushik Choudhuri, P. Anton van der Merwe ∗ Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom Abstract Despite intensive investigation we still do not understand how the T cell antigen receptor (TCR) tranduces signals across the plasma membrane, a process referred to as TCR triggering. Three basic mechanisms have been proposed, involving aggregation, conformational change, or segregation of the TCR upon binding pMHC ligand. Given the low density of pMHC ligand it remains doubtful that TCR aggregation initiates triggering, although it is likely to enhance subsequent signalling. Structural studies to date have not provided definitive evidence for or against a conformational change mechanism, but they have ruled out certain types of conformational change. Size-induced segregation of the bound TCR from inhibitory membrane tyrosine phosphatases seems to be required, but is probably not the only mechanism. Current evidence suggests that TCR triggering is initiated by a combination of segregation and conformational change, with subsequent aggregation contributing to amplification of the signal. © 2007 Elsevier Ltd. All rights reserved. Keywords: T cell receptor; TCR; Triggering; Signal transduction; Antigen recognition 1. Introduction The primary function of  T cells is to detect pathogen- derived peptides on the surface of other cells and then mount an appropriate response to eliminate the pathogens. The T cell antigen receptor (TCR) mediates this recognition by bind- ing to peptides in complex with MHC (pMHC) cell surface molecules. The TCR is a multisubunit assembly comprising a variable TCR heterodimer which binds to ligand, and the non- variable signal transduction subunits CD3, CD3, CD3, and TCR, which contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic domains. One of the ear- liest biochemical events that has been detected following TCR engagement by pMHC is phosphorylation of these TCR/CD3 ITAMs, which is mediated primarily by the Src family tyro- sine kinases (SFK) Lck and Fyn (reviewed in [1,2]). With some notable exceptions (see below), this step is believed to be essen- tial for signal transduction by the TCR [2]. Consequently, models of TCR triggering typically focus on explaining how TCR bind- ing to pMHC stimulates this ITAM phosphorylation. There is a large and confusing body of literature on TCR triggering, describing many different models [3–7]. All these models invoke one or more of three basic mechanisms of signal transduction across membranes, namely aggregation, conformational change, ∗ Corresponding author. Tel.: +44 1865 275593; fax: +44 1865 275593. E-mail address: anton.vandermerwe@path.ox.ac.uk (P.A. van der Merwe). and segregation [8]. We discuss each of these mechanisms in turn. 2. Aggregation It is well established that enforced aggregation of the TCR using either antibodies or soluble multimeric forms of pMHC is sufficient to initiate TCR triggering. This could generate a signal in a number of ways, including induced proximity between SFKs and TCR/CD3 ITAMs or proteins bound to these ITAMs. A key drawback of this model is that, under physiological circum- stances, agonist pMHC is present at very low surface densities. It fails to account for the reported ability of single agonist pMHC to induce TCR triggering [9,10]. A number of variants of the aggre- gation model have been proposed to address this difficulty. One model (reviewed in [3]) postulates that TCR/CD3 ITAM phos- phorylation results from simultaneous CD4 or CD8 coreceptor engagement of the same pMHC (Fig. 1a). As co-receptors are associated with Lck, this would bring Lck into close proximity with ITAMs and other substrates (such as the tyrosine kinase ZAP-70) associated with ITAMs. The major limitation of this coreceptor heterodimerization model is that TCR triggering can occur in the complete absence of coreceptors [11,12]. It follows that, while coreceptor engagement is likely to play an impor- tant modulatory role, there must be another mechanism of TCR triggering. A second proposed modification of the aggregation model postulated that TCR binding to pMHC resulted in a conforma- 1044-5323/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.smim.2007.04.005