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• W2034454780 abstract "T cell antigen recognition requires the binding of the T cell antigen receptor (TCR) to a complex between an antigen (usually peptide) and an MHC molecule (pep-MHC). This leads to a series of signaling events collectively referred to as TCR triggering, which is mediated by a group of TCR-associated transmembrane signaling molecules, the CD3 complex. Although it has been intensively studied, we still do not have satisfactory answers to two fundamental and related questions concerning TCR triggering. First, by what mechanism does TCR binding to pep-MHC result in triggering? Second, what binding property governs whether a particular TCR/pep-MHC interaction will lead to triggering? I discuss both of these questions here with special reference to two important recent papers (Baker and Wiley 2001Baker B.M Wiley D.C Immunity. 2001; 14 (this issue,): 681-692Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, Kalergis et al. 2001Kalergis A.M Boucheron N Doucey M.A Palmieri E Goyarts E.C Vegh Z Luescher I.F Nathenson S.G Nat. Immunol. 2001; 2: 229-234Crossref PubMed Scopus (235) Google Scholar), the former being published in this issue of Immunity. Many ideas concerning TCR triggering have been influenced by insights gleaned from other receptor systems, particularly receptors that, like the TCR, signal by stimulating tyrosine phosphorylation. However, the TCR/peptide-MHC interaction has unique features that should be borne in mind when considering possible answers to the questions posed above. First, the pep-MHC binding site on a TCR is generated in a quasi-random manner, and there is enormous diversity in the fine structure of interacting TCR and pep-MHC binding surfaces. Second, following crystallographic analysis of only a handful of pep-MHC complexes it is already clear that the orientation in which different TCRs engage pep-MHCs, although constrained to a certain extent, is quite variable (Garcia et al. 1999Garcia K.C Teyton L Wilson I.A Annu. Rev. Immunol. 1999; 17: 369-397Crossref PubMed Scopus (401) Google Scholar, Hennecke and Wiley 2001Hennecke J Wiley D.C Cell. 2001; 104: 1-4Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar). For example, the angle of engagement measured around the long axis of the TCR/pep-MHC complexes studied thus far differs by up to 35° (Hennecke and Wiley 2001Hennecke J Wiley D.C Cell. 2001; 104: 1-4Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar). Consequently, the structure of TCR/pep-MHC complexes is also likely to vary. Finally, T cells are required to, and are able to, recognize exceptionally low levels of specific pep-MHC on cells (see Kimachi et al. 1997Kimachi K Croft M Grey H.M Eur. J. Immunol. 1997; 27: 3310-3317Crossref PubMed Scopus (72) Google Scholar, and references therein); indeed, a single pep-MHC complex on a target cell may be sufficient. The models that have been proposed for TCR triggering can be divided into three groups depending on whether they invoke, as mechanisms of signal transduction, binding-induced multimerization, binding-induced conformational change, or neither (Figure 1). Multimerization models propose that ligand engagement brings together two or more TCR/CD3 complexes, which results in signaling through either induced proximity of associated signaling molecules or, as suggested more recently (Harder 2001Harder T Adv. Immunol. 2001; 77: 45-92Crossref PubMed Scopus (39) Google Scholar), the partitioning of aggregated TCR/CD3 complexes into lipid rafts that are themselves enriched in signaling molecules. Such models require the simultaneous engagement of at least two adjacent TCRs by pep-MHC and so fail to account for the fact that TCR triggering can occur at, and indeed is most efficient at (Lanzavecchia et al. 1999Lanzavecchia A Lezzi G Viola A Cell. 1999; 96: 1-4Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar), very low densities of pep-MHC. A possible solution to this difficulty was provided by two studies using soluble TCR and pep-MHC, which suggested that, following pep-MHC binding, TCR/pep-MHC complexes oligomerize (Reich et al. 1997Reich Z Boniface J.J Lyons D.S Borochov N Wachtel E.J Davis M.M Nature. 1997; 387: 617-620Crossref PubMed Scopus (196) Google Scholar, Alam et al. 1999Alam S.M Davies G.M Lin C.M Zal T Nasholds W Jameson S.C Hogquist K.A Gascoigne N.R Travers P.J Immunity. 1999; 10: 227-237Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar). The mechanism proposed was that, upon binding, the TCR or TCR/pep-MHC complex acquires the ability to bind directly to another TCR or TCR/pep-MHC complex. However, the structural diversity of TCR/pep-MHC complexes noted above raises doubts as to whether binding-induced self-association can be a general feature of TCR/pep-MHC interactions. Furthermore, individual TCR/pep-MHC complexes are quite heavily glycosylated and surrounded by CD3 and coreceptor glycoproteins (Rudd et al. 1999Rudd P.M Wormald M.R Stanfield R.L Huang M Mattsson N Speir J.A DiGennaro J.A Fetrow J.S Dwek R.A Wilson I.A J. Mol. Biol. 1999; 293: 351-366Crossref PubMed Scopus (201) Google Scholar), which would seem to preclude direct physical association of two or more TCR/pep-MHC complexes. These doubts are supported by a study reported in this issue that looked for evidence of binding-induced self-association in two soluble TCR/pep-MHC systems (Baker and Wiley 2001Baker B.M Wiley D.C Immunity. 2001; 14 (this issue,): 681-692Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). Using several sensitive techniques, including those used by Reich et al. 1997Reich Z Boniface J.J Lyons D.S Borochov N Wachtel E.J Davis M.M Nature. 1997; 387: 617-620Crossref PubMed Scopus (196) Google Scholar and Alam et al. 1999Alam S.M Davies G.M Lin C.M Zal T Nasholds W Jameson S.C Hogquist K.A Gascoigne N.R Travers P.J Immunity. 1999; 10: 227-237Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar, they convincingly rule out self-association in these systems. Taken together with other studies (e.g., Willcox et al. 1999Willcox B.E Gao G.F Wyer J.R Ladbury J.E Bell J.I Jakobsen B.K van der Merwe P.A Immunity. 1999; 10: 357-365Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar) that find no evidence of the complex binding kinetics that should be observed with self-association, this suggests that binding-induced self-association is not a general feature of TCR/pep-MHC interactions and is therefore unlikely to be the mechanism of TCR triggering. Conformational change models typically propose that, upon binding to pep-MHC, a TCR undergoes a conformational change that is somehow transmitted to the associated CD3 signaling machinery. The difficulty with these models is that they require, implausibly, that there is a conformational change in the TCR coupled to binding that is conserved in all TCRs in the face of enormous and semirandom variability in the TCR/pep-MHC binding interface. The fact that a number of recent structural studies have failed to reveal any evidence for conformational changes in the TCR other than adjustments at the binding interface would seem to rule out such models (Garcia et al. 1999Garcia K.C Teyton L Wilson I.A Annu. Rev. Immunol. 1999; 17: 369-397Crossref PubMed Scopus (401) Google Scholar, Hennecke and Wiley 2001Hennecke J Wiley D.C Cell. 2001; 104: 1-4Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar). A more plausible conformational change model has been proposed recently that is compatible with the available structural data (Ding et al. 1999Ding Y.-H Baker B.M Garboczi D.N Biddison W.E Wiley D.C Immunity. 1999; 11: 45-56Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar). According to this dimer conformational change model, two TCRs are present as a preformed dimer (i.e., two αβTCRs), and simultaneous binding of each TCR to specific pep-MHC alters the relative orientation of the two TCRs. Interest in the latter model has been stimulated by evidence for the existence of preformed TCR dimers on the T cell surface (Fernandez-Miguel et al. 1999Fernandez-Miguel G Alarcon B Iglesias A Bluethmann H Alvarez-Mon M Sanz E de la Hera A Proc. Natl. Acad. Sci. USA. 1999; 96: 1547-1552Crossref PubMed Scopus (111) Google Scholar). While the dimer adjustment model, like multimerization models, requires the simultaneous engagement of two adjacent TCRs, the presence of preformed TCR dimers should significantly increase the likelihood of this event. The evidence and arguments outlined above have increased interest in models of TCR triggering that do not invoke conformational change or multimerization (Figure 1). One such model postulates that triggering results from the heterodimerization of the TCR with the CD8 or CD4 coreceptors following binding to the same pep-MHC complex, thereby inducing proximity between the TCR/CD3 complex and coreceptor-associated signaling molecules. Support for such a model was provided by the observation that monovalent soluble pep-MHC can trigger T cells provided that they express CD8 (Delon et al. 1998Delon J Gregoire C Malissen B Darche S Lemaitre F Kourilsky P Abastado J.P Trautmann A Immunity. 1998; 9: 467-473Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). However, coreceptor heterodimerization cannot be a general mechanism since TCR triggering can occur in cells entirely lacking coreceptors. The raft association model (not shown in Figure 1) postulates that TCR engagement leads to association of that TCR/CD3 complex with lipid rafts (Lanzavecchia et al. 1999Lanzavecchia A Lezzi G Viola A Cell. 1999; 96: 1-4Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar). However, no convincing mechanism has been proposed to explain how engagement of a single TCR/CD3 leads to raft association. The kinetic-segregation model (Davis and van der Merwe 1996Davis S.J van der Merwe P.A Immunol.Today. 1996; 17: 177-187Scopus (329) Google Scholar, van der Merwe et al. 2000van der Merwe P.A Davis S.J Shaw A.S Dustin M.L Semin.Immunol. 2000; 12: 5-21Google Scholar) proposes that pep-MHC binding induces triggering by tethering the TCR/CD3 complex within a zone of close membrane contact in which tyrosine phosphorylation is favored. While the TCR/CD3 complex is held in this zone, the sequence of phosphorylation and phosphorylation-dependent steps required for TCR triggering can proceed. The model proposes that tyrosine phosphorylation is favored because the formation of a close-contact zone is accompanied by exclusion or segregation from the zone of membrane tyrosine phosphatases, many of which, like CD45 and CD148, have large ectodomains that could drive exclusion. It is important to stress that the segregation proposed here is on a much smaller scale than the large-scale segregation of cell-surface molecules characteristic of the immunological synapse that forms between an activated T cell and APCs or target cells (Monks et al. 1998Monks C.R Freiberg B.A Kupfer H Sciaky N Kupfer A Nature. 1998; 395: 82-86Crossref PubMed Scopus (1896) Google Scholar, Grakoui et al. 1999Grakoui A Bromley S.K Sumen C Davis M.M Shaw A.S Allen P.M Dustin M.L Science. 1999; 285: 221-227Crossref PubMed Scopus (2456) Google Scholar, Stinchcombe et al. 2001Stinchcombe J.C Barral D.C Mules E.H Booth S Hume A.N Machesky L.M Seabra M.C Griffiths G.M J. Cell Biol. 2001; 152: 825-834Crossref PubMed Scopus (308) Google Scholar). The latter follows and depends upon TCR triggering and so cannot be the mechanism of TCR triggering (van der Merwe et al. 2000van der Merwe P.A Davis S.J Shaw A.S Dustin M.L Semin.Immunol. 2000; 12: 5-21Google Scholar). It has been proposed instead that large-scale segregation is required for, or the result of a process required for, polarized secretion by T cells toward antigen-presenting or target cells (Davis and van der Merwe 2001Davis, S.J., and van der Merwe, P.A. (2001). Curr. Biol., in press.Google Scholar). What feature of a TCR/pep-MHC interaction determines whether pep-MHC binding will result in TCR triggering? The notion that the nature of the response is determined by the particular structural change induced in a TCR can probably be ruled out, for two reasons. First, the highly variable structure of TCR/pep-MHC interfaces makes it implausible that the same conformational changes are induced in all TCRs in response to ligand binding. Second, there is no evidence of structural changes in TCR/pep-MHC complexes that correlate with the functional outcome of binding (Garcia et al. 1999Garcia K.C Teyton L Wilson I.A Annu. Rev. Immunol. 1999; 17: 369-397Crossref PubMed Scopus (401) Google Scholar, Hennecke and Wiley 2001Hennecke J Wiley D.C Cell. 2001; 104: 1-4Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar). Particularly convincing are the demonstrations that the structure of a given TCR is essentially the same whether bound to agonist, superagonist, or antagonist pep-MHC (Ding et al. 1999Ding Y.-H Baker B.M Garboczi D.N Biddison W.E Wiley D.C Immunity. 1999; 11: 45-56Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar, Degano et al. 2000Degano M Garcia K.C Apostolopoulos V Rudolph M.G Teyton L Wilson I.A Immunity. 2000; 12: 251-261Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar). It would seem more plausible that the TCR response is determined by a binding property related to binding strength, such as affinity or half-life. It is unlikely for two reasons that the affinity per se is the key property. First, differences in affinity can only be detected by the T cell as a difference in the number of engaged TCRs, which fails to account for situations in which only a few pep-MHC complexes are sufficient to trigger a T cell. Second, it is difficult to envisage how the TCR could discriminate between ligands with small differences in affinity, as is the case. More attractive is the notion that the T cell response is dependent on the half-life of the TCR/pep-MHC interaction. By coupling a dependence on half-life with a requirement for several consecutive signaling steps for TCR triggering, the TCR can discriminate very effectively between pep-MHCs that differ only slightly in their TCR binding half-lives (McKeithan 1995McKeithan T.W Proc. Natl. Acad. Sci. USA. 1995; 92: 5042-5046Crossref PubMed Scopus (670) Google Scholar). A number of studies have measured the affinity and kinetics of interactions between soluble forms of TCR and pep-MHC and attempted to correlate these properties with the functional outcome of the interaction. While there is a crude correlation between binding strength as measured by affinity or half-life and T cell response, this correlation tends to break down when TCR/pep-MHC interactions with smaller (2- to 5-fold) differences in affinity or half-life are compared. One possible explanation for this is suggested by the recent study by Kalergis et al. 2001Kalergis A.M Boucheron N Doucey M.A Palmieri E Goyarts E.C Vegh Z Luescher I.F Nathenson S.G Nat. Immunol. 2001; 2: 229-234Crossref PubMed Scopus (235) Google Scholar. They measured the dissociation half-life of pep-MHC class I tetramers from T cells and correlated these with functional responses. In the two systems studied, they found that TCR/pep-MHC interactions with the longest half-lives did not give the best functional response. Importantly, a TCR mutation that reduced the half-lives of “long half-life” pep-MHCs actually enhanced TCR triggering. Thus, there appears to be an optimal TCR/pep-MHC half-life or “dwell time” with longer and shorter half-lives correlating with poorer responses. This was predicted by, and provides support for, the serial triggering model (Lanzavecchia et al. 1999Lanzavecchia A Lezzi G Viola A Cell. 1999; 96: 1-4Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar), which postulates that a certain threshold number of TCRs needs to be engaged for T cell activation, and that each pep-MHC can serially engage multiple TCRs. It follows that pep-MHCs that engage TCRs with a half-life longer than that required for triggering will be less effective agonists because they will trigger fewer TCRs in a given time period. There remain, however, data that are not explained by the optimal dwell time/serial triggering model. For example, it has been observed that TCR/pep-MHC interactions with very similar half-lives can have very different functional outcomes (Baker et al. 2000Baker M.B Gagnon J.S Biddison E.W Wiley C.D Immunity. 2000; 13: 475-484Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, Baker et al. 2001Baker B.M Turner R.V Gagnon S.J Wiley D.C Biddison W.E J. Exp. Med. 2001; 193: 551-562Crossref PubMed Scopus (74) Google Scholar). One possible explanation for these discrepancies is that the binding half-life measured in solution (where at least one of the molecules is soluble) does not accurately reflect the half-life of the TCR/pep-MHC interaction at the cell-cell interface. One crucial difference in the interactions between soluble molecules and between their membrane-tethered counterparts is that in the latter case the interactions are subjected to mechanical stress, i.e., there will be some traction force applied to the TCR/pep-MHC bond. This force arises from one or more of several sources including thermal fluctuation in the membranes, repulsive forces between the membranes, and movement of the T cell relative to the APC or target cell. Crucially, the half-life of an interaction decreases when subjected to mechanical stress, but the extent to which it decreases will vary between interactions. Where studied, the binding property that correlates best with the mechanical strength of a bond was the activation enthalpy (Leckband 2000Leckband D Annu. Rev. Biophys. Biomol. Struct. 2000; 29: 1-26Crossref PubMed Scopus (398) Google Scholar). It may be significant therefore that TCR/pep-MHC interactions have a remarkably high activation enthalpy (Boniface et al. 1999Boniface J.J Reich Z Lyons D.S Davis M.M Proc. Natl. Acad. Sci. USA. 1999; 96: 11446-11451Crossref PubMed Scopus (157) Google Scholar, Willcox et al. 1999Willcox B.E Gao G.F Wyer J.R Ladbury J.E Bell J.I Jakobsen B.K van der Merwe P.A Immunity. 1999; 10: 357-365Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar), suggesting considerable mechanical strength. This is consistent with the observation that T cells can extract and internalize engaged pep-MHC from target cells (Huang et al. 1999Huang J.-F Yang Y Sepulveda H Shi W Hwang I Peterson P.A Jackson M.R Sprent J Cai Z Science. 1999; 286: 952-954Crossref PubMed Scopus (363) Google Scholar) and tend to leave behind TCRs when forcibly detached from planar bilayers presenting pep-MHC to which they bind (Dustin et al. 1996Dustin M.L Miller J.M Ranganath S Vignali D.A Viner N.J Nelson C.A Unanue E.R J. Immunol. 1996; 157: 2014-2021PubMed Google Scholar). These observations suggest that TCR/pep-MHC half-lives at the cell:cell interface may not always correlate with half-lives measures in solution, and raise the question as to whether the mechanical strength of a TCR/pep-MHC interaction, by determining the half-life under mechanical stress, is an important determinant of TCR triggering. Despite extensive efforts, the mechanism of TCR triggering remains poorly understood, and there are a number of competing models. There are major difficulties with more traditional models such as those postulating binding-induced conformational change of the TCR or binding induced-multimerization. Newer models, such as the dimer conformational change, raft-association, and kinetic-segregation models, have been proposed that are compatible with the available data, but they have yet to be rigorously tested." @default.
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• W2034454780 title "The TCR Triggering Puzzle" @default.
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