The T Cell Receptor for Antigen: Signaling and Ligand Discrimination (2001)

T cell receptor complementarity-determining region immune tyrosine-based activation motif linker of activated T-cells extracellular signal-regulated kinase SH2 domain-containing protein-tyrosine phosphatase A defining characteristic of the vertebrate adaptive immune system is its specificity, which arises from clonally distributed receptors encoded by gene segments that undergo somatic rearrangement in B and T lymphocytes (1Davis M.M. Bjorkman P.J. Nature. 1988; 334: 395-402Crossref PubMed Scopus (2466) Google Scholar,2Max E.E. Paul W.E. Fundamental Immunology. 4th Ed. Lippincott-Raven Publishers, Philadelphia1999: 111-182Google Scholar). 1Because of space limitations, reviews have been cited in many places instead of primary references. I apologize to those colleagues whose original work could not be directly referenced for this reason. B lymphocyte receptors are membrane-bound immunoglobulin molecules that as a group react with a biochemically diverse array of ligands. In marked contrast, most receptors expressed by the major CD4+ and CD8+subsets of T lymphocytes (αβ TCR)2 are narrowly focused on small protein fragments bound to cell surface molecules encoded by major histocompatibility complex (MHC) class I or class II genes (3Germain R.N. Cell. 1994; 76: 287-299Abstract Full Text PDF PubMed Scopus (1272) Google Scholar). T cell responses to foreign organisms thus pose a major conceptual challenge (4Germain R.N. Stefanova I. Annu. Rev. Immunol. 1999; 17: 467-522Crossref PubMed Scopus (375) Google Scholar). These lymphocytes develop effector activity when only a few hundred of the >105 MHC-encoded molecules on the plasma membrane of a cell are occupied by peptides derived from an infectious agent (3Germain R.N. Cell. 1994; 76: 287-299Abstract Full Text PDF PubMed Scopus (1272) Google Scholar, 4Germain R.N. Stefanova I. Annu. Rev. Immunol. 1999; 17: 467-522Crossref PubMed Scopus (375) Google Scholar). The remaining MHC molecules contain peptides from self-proteins that may differ from the foreign peptides by only a single amino acid (5Matsumura M. Fremont D.H. Peterson P.A. Wilson I.A. Science. 1992; 257: 927-934Crossref PubMed Scopus (650) Google Scholar, 6Stern L.J. Wiley D.C. Structure. 1994; 2: 245-251Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar). Thus, a fundamental question is how TCR signaling can be both sensitive and specific for foreign determinants when there is a 103–104 greater concentration of structurally related self-ligands on the interacting cell membrane. Neither genetic nor developmental factors fully account for this capacity. TCR combining sites are generated anew in each individual by DNA rearrangement. The proteins from which self-peptides derive can be polymorphic and are mostly unlinked to TCR genes, and MHC molecules are highly diverse in structure and also unlinked to TCR loci. These are all features that prevent genetic matching of the TCR repertoire with the universe of ligands that it faces. Developing T cells do undergo a process termed negative selection, in which many clones with the most highly self-reactive TCR are eliminated by apoptosis (7Robey E. Fowlkes B.J. Annu. Rev. Immunol. 1994; 12: 675-705Crossref PubMed Scopus (450) Google Scholar). However, maturation of a precursor T cell requires TCR-dependent signals (7Robey E. Fowlkes B.J. Annu. Rev. Immunol. 1994; 12: 675-705Crossref PubMed Scopus (450) Google Scholar), yielding a repertoire with at least the capacity for self-recognition if not response. The basis for TCR antigen discrimination and sensitivity must thus lie in how receptor-ligand interactions are coupled to intracellular signaling pathways. We have an increasingly detailed knowledge of the biochemical cascade initiated by this recognition process (8Weiss A. Littman D.R. Cell. 1994; 76: 263-274Abstract Full Text PDF PubMed Scopus (1955) Google Scholar, 9Clements J.L. Boerth N.J. Lee J.R. Koretzky G.A. Annu. Rev. Immunol. 1999; 17: 89-108Crossref PubMed Scopus (173) Google Scholar). Image analysis has revealed a complex spatiotemporal reorganization of lymphocyte proteins during responses to membrane-bound TCR ligands (10Monks C.R. Freiberg B.A. Kupfer H. Sciaky N. Kupfer A. Nature. 1998; 395: 82-86Crossref PubMed Scopus (1972) Google Scholar, 11Grakoui 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 (2540) Google Scholar, 12Krummel M.F. Sjaastad M.D. Wulfing C. Davis M.M. Science. 2000; 289: 1349-1352Crossref PubMed Scopus (330) Google Scholar, 13Wulfing C. Sjaastad M.D. Davis M.M. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6302-6307Crossref PubMed Scopus (242) Google Scholar). The affinity and rate constants that characterize the interaction of soluble versions of TCRs and their ligands have been measured (14Ward E.S. Qadri A. Curr. Opin. Immunol. 1997; 9: 97-106Crossref PubMed Scopus (19) Google Scholar). Finally, differences in proximal TCR signaling and membrane protein reorganization have been documented following exposure of T cells to sets of related ligands (4Germain R.N. Stefanova I. Annu. Rev. Immunol. 1999; 17: 467-522Crossref PubMed Scopus (375) Google Scholar, 11Grakoui 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 (2540) Google Scholar) and then correlated with TCR-ligand affinities. These observations have led to a “kinetic” model of ligand discrimination by the TCR that enjoys broad support (15McKeithan T.W. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5042-5046Crossref PubMed Scopus (715) Google Scholar). However this important concept does not explain how TCR engagement leads to initiation of signaling or how differences in TCR binding to related ligands produce distinct phosphorylation patterns and biological responses. This minireview will highlight what is known about these issues and also point out areas of controversy bearing on this fundamental aspect of T cell biology. The α and β chains of the TCR are Type I integral membrane proteins with a membrane-distal immunoglobulin V-like domain and a membrane-proximal immunoglobulin C-like domain. The combining site is composed of germ line-encoded complementarity-determining regions (CDR) 1 and 2 of each chain and the two CDR3 regions that include germ line- and non-germ line-encoded residues. There is a relatively stereotypic docking position of the αβ heterodimer on MHC proteins that orients the CDR3 region for contact with exposed peptide side chains (16Garcia K.C. Teyton L. Wilson I.A. Annu. Rev. Immunol. 1999; 17: 369-397Crossref PubMed Scopus (423) Google Scholar), which determines TCR fine specificity. The receptor heterodimer is expressed in conjunction with a set of invariant integral membrane proteins termed the CD3ζ complex. The α and β cytoplasmic tails are short and devoid of recognizable signaling motifs, but the other subunits of the minimal octameric complex (α, β, δ, γ, 2 CD3ε, and 2 ζ) each contain one or more copies of an amino acid sequence (Y(2X)I/L(4–6X)Y(2X)I/L) termed the immune tyrosine-based activation motif (ITAM) (17Chan A.C. Irving B.A. Weiss A. Curr. Opin. Immunol. 1992; 4: 246-251Crossref PubMed Scopus (41) Google Scholar). ITAMs are the sites of Src family kinase tyrosine phosphorylation, a key early event in the TCR signaling cascade. CD8 and CD4 are membrane glycoproteins expressed by T cells that bind MHC class I and MHC class II molecules, respectively, but lack the peptide specificity of the TCR. The interaction of CD4 and CD8 with their MHC ligands through structurally analogous sites (18Salter R.D. Benjamin R.J. Wesley P.K. Buxton S.E. Garrett T.P. Clayberger C. Krensky A.M. Norment A.M. Littman D.R. Parham P. Nature. 1990; 345: 41-46Crossref PubMed Scopus (474) Google Scholar, 19König R. Huang L.-Y. Germain R.N. Nature. 1992; 356: 796-798Crossref PubMed Scopus (321) Google Scholar, 20Cammarota G. Scheirle A. Takacs B. Doran D.M. Knorr R. Bannworth W. Guardiola J. Sinigaglia F. Nature. 1992; 356: 799-801Crossref PubMed Scopus (247) Google Scholar) facilitates T cell activation. These proteins are believed to form a ternary complex with the TCR and bound MHC ligand, hence the term “coreceptors” (21Portoles P. Rojo J.M. Janeway Jr., C.A. Immunol. Rev. 1989; 109: 77-92Crossref PubMed Scopus (52) Google Scholar). Although some recent data on CD4-MHC class II interactions have raised questions about this model (22Crawford F. Kozono H. White J. Marrack P. Kappler J. Immunity. 1998; 8: 675-682Abstract Full Text Full Text PDF PubMed Scopus (409) Google Scholar, 23Hamad A.R. O'Herrin S.M. Lebowitz M.S. Srikrishnan A. Bieler J. Schneck J. Pardoll D. J. Exp. Med. 1998; 188: 1633-1640Crossref PubMed Scopus (87) Google Scholar), the bulk of structural data and many biological experiments support the coreceptor view (24Luescher I.F. Vivier E. A. J. F. B. P. Nature. 1995; PubMed Scopus Google Scholar, J. Exp. Med. 2000; PubMed Scopus Google Scholar). The TCR and its ligands are membrane-bound and receptor engagement the of two cell has that the region of contact of individual proteins distinct (10Monks C.R. Freiberg B.A. Kupfer H. Sciaky N. Kupfer A. Nature. 1998; 395: 82-86Crossref PubMed Scopus (1972) Google Scholar, 11Grakoui 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 (2540) Google M. Wulfing C. Sumen C. Davis M.M. R. B Sci. 2000; PubMed Scopus Google Scholar, M.L. Immunol. 2000; PubMed Scopus Google Scholar, J. Germain R.N. Curr. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). This contact is termed the J. Germain R.N. Curr. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). with of through on T cells and molecules on cells 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 (2540) Google Scholar, M.L. Immunol. 2000; PubMed Scopus Google Scholar), and for recognition R. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). TCR engagement then leads to the of a of the a region of TCR (10Monks C.R. Freiberg B.A. Kupfer H. Sciaky N. Kupfer A. Nature. 1998; 395: 82-86Crossref PubMed Scopus (1972) Google Scholar, 11Grakoui 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 (2540) Google Scholar). of cells protein M.F. Sjaastad M.D. Wulfing C. Davis M.M. Science. 2000; 289: 1349-1352Crossref PubMed Scopus (330) Google Scholar) that TCR are distributed in that a more the for of the (10Monks C.R. Freiberg B.A. Kupfer H. Sciaky N. Kupfer A. Nature. 1998; 395: 82-86Crossref PubMed Scopus (1972) Google with a of MHC ligands on the requires of the and signaling from the of TCR M.L. Immunol. 2000; PubMed Scopus Google Scholar), some protein patterns may directly from the of molecules bound to ligands on an cell membrane Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). The of that the receptor of the is not for initiation of (4Germain R.N. Stefanova I. Annu. Rev. Immunol. 1999; 17: 467-522Crossref PubMed Scopus (375) Google Scholar, J. Germain R.N. Curr. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). then what is the for the of a complex have been the the of the of the T cell and A. J. Exp. 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J. 1998; PubMed Scopus Google Scholar). of side chain can be This an for the of and is at the of TCR these proteins be to to membrane as the TCR or these integral membrane are with to their affinity for the will be The molecules could then regions of membrane. a these molecules to have been in which not the of of the Thus, an of a of with as the site of early and TCR there are as as conceptual to these The for most of the The of and the signaling cascade do not by explain to the small measured differences in binding affinity of and ligands (14Ward E.S. Qadri A. Curr. Opin. Immunol. 1997; 9: 97-106Crossref PubMed Scopus (19) Google Scholar). how this is to from of Immunity. 1995; 2: Full Text PDF PubMed Scopus (246) Google Scholar, J. Allen P.M. Annu. Rev. Immunol. PubMed Scopus Google Scholar, J. Germain R.N. Immunol. 8: PubMed Scopus Google Scholar). These are in which only one or a few amino in the peptide or MHC differ from those in the known complex for a TCR. ligands of this from the original to to at ligand some but not all effector responses by the to of responses but to with responses to to ligand on T cell of early TCR signaling has revealed that and the of a form of in the with molecules that nor (4Germain R.N. Stefanova I. Annu. Rev. Immunol. 1999; 17: 467-522Crossref PubMed Scopus (375) Google Scholar). in contrast, produce both this and an or greater of fully with in a of the two signals in a to the with or these data a of ligand structure on the signaling on the that ligands have a affinity for a a (15McKeithan T.W. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5042-5046Crossref PubMed Scopus (715) Google Scholar) the of in the of TCR recognition (15McKeithan T.W. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5042-5046Crossref PubMed Scopus (715) Google Scholar). This model that signaling in a initiation of receptor with at each of the cascade. of receptor not only the system but also has a on of the signaling to the This both signaling and the of for this model has from of the binding of soluble TCR with soluble ligands (14Ward E.S. Qadri A. Curr. Opin. Immunol. 1997; 9: 97-106Crossref PubMed Scopus (19) Google Scholar). not of these data an or and ligand when the of signaling as by and phosphorylation This a for the of phosphorylation as as the of activation with affinity and on the that phosphorylation of and activation of phosphorylation and binding Shaw A.S. Allen P.M. Science. 1998; PubMed Scopus Google Scholar). are the that differences in of TCR distinct signaling that can phosphorylation, TCR by binding ligands must be to Src these TCR that phosphorylation as the model the of the tyrosine on could be by in the of the occupied TCR of TCRs the of the from this phosphatase does not with ligands 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 (2540) Google Scholar). However, patterns of phosphorylation are with at ligands of TCR that when is with TCR R. S. S. Curr. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, Bromley S.K. Dustin M.L. M.L. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar). This it to phosphorylation to is that Src family in T of the tyrosine requires the of both this kinase and the Src kinase in the membrane that TCRs are not is to these its docking protein is D. A. E. P. J. A. I. J. B. B. J. Exp. Med. 2000; PubMed Scopus Google Scholar, M. S. A. M. Nature. 2000; PubMed Scopus Google Scholar). this account for the of kinase TCR-ligand can be with data to produce a more complex but TCR engagement leads to the tyrosine phosphorylation of the phosphatase U. D. Cell. 1994; PubMed Scopus Google Scholar). We have that this binding of the to or not the TCR in question has been Stefanova I. Germain R.N. Janeway Jr., C.A. Immunity. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). B. M. W. E. R. and R. N. for This binding is by activation of the phosphatase and then the of the and Stefanova I. Germain R.N. Janeway Jr., C.A. Immunity. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, D.R. R. R.J. M. G. A.C. M.L. Science. PubMed Scopus Google Scholar, U. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google the of this binding to the TCR is related to the of the TCR ligand for and for the be to be of phosphorylation and its to the TCR. The in phosphatase binding to the TCR the of recognition has been to a of whose phosphorylation of binding of to the SH2 TCR Thus, two in TCR engagement with to TCR signaling and to receptors from but not the of by of in there is a of TCRs whose by is negative of TCR-dependent T cell activation is with the concept that by combining negative and with Stefanova I. Germain R.N. Janeway Jr., C.A. Immunity. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), both sensitivity and discrimination by the receptor can be C. J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus (52) Google Scholar). Finally, these data that the with these a of phosphorylation, from phosphorylation that is by ligands then to the of the do differences in the of TCR binding to in the of A from data coreceptor to signaling J. J. Germain R.N. J. Exp. Med. 1997; PubMed Scopus Google Scholar, J. J. Exp. Med. 1998; PubMed Scopus Google Scholar). are from the of surface TCR. Thus, some must ligand binding and the of the TCR with a the rate of of in the plasma membrane is or if binding of the coreceptor to an TCR is a event and requires many to be of ternary will only with and not ligands. ligand binding is to coreceptor interaction of this with the TCR complex could to phosphorylation of the activated in the TCR complex to R. W. J.M. J.L. A. J. Exp. Med. 1999; PubMed Scopus Google Scholar). phosphorylation is key to and with the to activation. the other if the ligand from the coreceptor binding to form a ternary complex not and the This leads to the phosphorylation of and the binding of this phosphatase to the molecules of as as TCR. phosphorylation of proteins by the activated engagement of the SH2 of the bound phosphatase This in activation and of tyrosine from proteins in the TCR and The is a receptor with a phosphorylation of the major in intracellular signaling have been the interactions these molecules have been and the that to these have been the most fundamental of T their capacity for ligand has not been for in detailed In this is of receptors has been the primary to TCR signaling pathways. binding to does not have the of MHC interaction nor does it support the of the key CD4 or CD8 many have the of TCR ligands for signaling and to the of to the analysis of the spatiotemporal features of TCR-dependent lymphocyte activation. these have not the or the in the cascade to gene activation in T We have some of what of to of but not or that the of TCR-ligand interaction is out by individual receptors or small of these TCRs is of or these and signaling is for gene activation proximal tyrosine phosphorylation can be at these of protein the plasma membrane and the of is also to in the view of these of the of the TCR and ligand, the TCR recognition and activation is a major in the of the data on the and are to an that a of the and their will be to to the in of a process that is one of the defining features of the adaptive immune