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The immunological synapse: required for T cell receptor signalling or directing T cell effector function?

2001; Elsevier BV; Volume: 11; Issue: 8 Linguagem: Inglês

10.1016/s0960-9822(01)00165-8

1879-0445

Simon J. Davis, P. Anton van der Merwe,

Immunotherapy and Immune Responses

The discovery of the immunological synapse is one of the more striking developments in T cell biology in recent years. The immunological synapse forms at the interface between T cells and antigen-presenting cells (APCs) or target cells. It is characterised by the large-scale segregation of cell surface molecules into concentric zones, forming a bull's eye pattern several microns in diameter (reviewed in [1.van der Merwe P.A Davis S.J Shaw A.S Dustin M.L Cytoskeletal polarization and redistribution of cell-surface molecules during T cell antigen recognition.Semin Immunol. 2000; 12: 5-21Crossref PubMed Scopus (239) Google Scholar]). In their excellent review of recent work on the immunological synapse, published in Current Biology[2.Delon J Germain R.N Information transfer at the immunological synapse.Curr Biol. 2000; 10: R923-R933Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar], Delon and Germain correctly stress, as we have [1.van der Merwe P.A Davis S.J Shaw A.S Dustin M.L Cytoskeletal polarization and redistribution of cell-surface molecules during T cell antigen recognition.Semin Immunol. 2000; 12: 5-21Crossref PubMed Scopus (239) Google Scholar], that synapse formation follows, and is dependent on, T cell antigen receptor (TCR) signalling. Although this indicates that synapse formation is not required for TCR signalling, they nevertheless conclude, as have others [3.Dustin M.L Chan A.C Signaling takes shape in the immune system.Cell. 2000; 103: 283-294Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar], that a principal function of the synapse is to "stabilise signal transduction by the TCR for the prolonged periods of time required for gene activation" [2.Delon J Germain R.N Information transfer at the immunological synapse.Curr Biol. 2000; 10: R923-R933Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar]. As we discuss below, recent work suggests that the dynamics of TCR signalling are likely to be profoundly altered by synapse formation. Rather than being important for TCR signalling, we argue that immunological synapse formation is linked instead to the delivery of secondary T cell signalling and effector functions, such as directed secretion. The protein kinase p56lck, which phosphorylates the TCR upon antigen engagement, and the phosphatase, CD45, which maintains p56lck in a primed or activatable state, are both required for TCR signalling [1.van der Merwe P.A Davis S.J Shaw A.S Dustin M.L Cytoskeletal polarization and redistribution of cell-surface molecules during T cell antigen recognition.Semin Immunol. 2000; 12: 5-21Crossref PubMed Scopus (239) Google Scholar]. Kinetic models [4.McKeithan T.W Kinetic proofreading in T-cell receptor signal transduction.Proc Natl Acad Sci USA. 1995; 92: 5042-5046Crossref PubMed Scopus (670) Google Scholar, 5.Davis S.J van der Merwe P.A The structure and ligand interactions of CD2: implications for T-cell function.Immunol Today. 1996; 17: 177-187Abstract Full Text PDF PubMed Scopus (329) Google Scholar, 6.Rabinowitz J.D Beeson C Lyons D.S Davis M.M McConnell H.M Kinetic discrimination in T-cell activation.Proc Natl Acad Sci USA. 1996; 93: 1401-1405Crossref PubMed Scopus (235) Google Scholar] predict that signalling will be highly sensitive to the distances over which such molecules have to diffuse to reach their substrates. According to recent studies [7.Leupin O Zaru R Laroche T Muller S Valitutti S Exclusion of CD45 from the T-cell receptor signaling area in antigen-stimulated T lymphocytes.Curr Biol. 2000; 10: 277-280Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, 8.Johnson K.G Bromley S.K Dustin M.L Thomas M.L A supramolecular basis for CD45 tyrosine phosphatase regulation in sustained T cell activation.Proc Natl Acad Sci USA. 2000; 97: 10138-10143Crossref PubMed Scopus (162) Google Scholar], there is no visible segregation of the TCR from CD45 at the time when TCR signalling peaks, shortly after antigen encounter. This situation changes dramatically upon synapse formation, however, whereupon CD45 is excluded from the 0.5–1μM central region within which the TCR and p56lck are sequestered. It is highly unlikely that the enzymology of TCR triggering accommodates two kinetically distinct signalling mechanisms, or one mechanism that is dependent on CD45 and another that is not. Rather than sustaining signalling, therefore, the observed reorganisation seems to us more likely to be detrimental to TCR signalling. It is a formal possibility that the dramatic images of the synapse exaggerate the degree of molecular segregation and that TCR signalling continues unabated after synapse formation. However, this would still imply that the gross structural features of the synapse have little to do with TCR signalling. What then might the purpose of the immunological synapse be? A key role for this structure emphasised in earlier studies is directed secretion, which focuses effector functions, such as cytokine secretion and cell killing, on the antigen-presenting or target cell, reducing bystander effects [9.Kupfer A Singer S.J Cell biology of cytotoxic and helper T cell functions: immunofluorescence microscopic studies of single cells and cell couples.Annu Rev Immunol. 1989; 7: 309-337Crossref PubMed Scopus (221) Google Scholar, 10.Paul W.E Seder R.A Lymphocyte responses and cytokines.Cell. 1994; 76: 241-251Abstract Full Text PDF PubMed Scopus (1660) Google Scholar]. We propose that directed secretion is linked to large-scale molecular segregation at the synapse for two reasons. First, in order for the effects of directed secretion to be restricted to the presenting or target cell it is important that the granule contents of the T cell be retained at the interface. The narrow interface and adhesion ring around the central portion of the synapse may serve this purpose and explains why cytokine receptors are relatively small. Second, it seems likely that remodelling of the cytoskeleton accompanies, and is required for, directed secretion, and that associated cell-surface molecules become segregated as a consequence of these processes. Support for a link between synapse formation and directed secretion is provided by the recent demonstration that, at the interface between cytotoxic T cells and their targets cells, secretory granules congregate next to, and release their contents into, the central portion of the synapse [11.Stinchcombe J.C Barral Duarte C Mules E.H Booth S Hume A.N Machesky L.M et al.Rab27a is required for regulated secretion in cytotoxic T lymphocytes.J Cell Biol. 2001; 152: 825-834Crossref PubMed Scopus (308) Google Scholar]. Although synapse formation may favour processes other than TCR signalling, this does not rule out a critical role for the synapse in signalling, particularly via receptors other than the TCR. Significantly, the expression of cytokine receptors or the involvement of co-stimulatory molecules appear to be better correlates of the rate of T cell commitment by naı̈ve and effector cells, than levels of TCR triggering per se, as measured by TCR internalisation [12.Iezzi G Karjalainen K Lanzavecchia A The duration of antigenic stimulation determines the fate of naive and effector T cells.Immunity. 1998; 8: 89-95Abstract Full Text Full Text PDF PubMed Scopus (708) Google Scholar]. A clear temporal and functional correlation exists between T cell–APC conjugation, synapse formation and T cell activation which is readily explained by secondary signalling processes involving, for example, cytokine–cytokine receptor and co-stimulatory receptor–ligand interactions. These processes will be enhanced by extended cell–cell contact and are likely to depend on the cytoskeletal rearrangements and directed secretion that are the hallmark of synapse formation [1.van der Merwe P.A Davis S.J Shaw A.S Dustin M.L Cytoskeletal polarization and redistribution of cell-surface molecules during T cell antigen recognition.Semin Immunol. 2000; 12: 5-21Crossref PubMed Scopus (239) Google Scholar]. TCR signalling is perhaps best viewed as the first in a series of obligatory checkpoints leading to full T cell activation and commitment. Rather than being the site of prolonged TCR signalling, the synapse seems to us more likely to mediate both the secondary signalling events leading to full T cell activation and the delivery of T cell effector functions.