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• W2056315052 abstract "Structural studies on T cell receptors (TCRs) specific for foreign antigens demonstrated a remarkably similar topology characterized by a central, diagonal TCR binding mode that maximizes interactions with the MHC bound peptide. However, three recent structures involving autoimmune TCRs demonstrated unusual interactions with self-peptide/MHC complexes. Two TCRs from multiple sclerosis patients bind with unconventional topologies, and both TCRs are shifted toward the peptide N terminus and the MHC class II β chain helix. A TCR from the experimental autoimmune encephalomyelitis (EAE) model binds in a conventional orientation, but the structure is unusual because the self-peptide only partially fills the binding site. For all three TCRs, interaction with the MHC bound self-peptide is suboptimal, and only two or three TCR loops contact the peptide. Optimal TCR binding modes confer a competitive advantage for antimicrobial T cells during an infection, whereas altered binding properties may permit survival of a subset of autoreactive T cells during thymic selection. Structural studies on T cell receptors (TCRs) specific for foreign antigens demonstrated a remarkably similar topology characterized by a central, diagonal TCR binding mode that maximizes interactions with the MHC bound peptide. However, three recent structures involving autoimmune TCRs demonstrated unusual interactions with self-peptide/MHC complexes. Two TCRs from multiple sclerosis patients bind with unconventional topologies, and both TCRs are shifted toward the peptide N terminus and the MHC class II β chain helix. A TCR from the experimental autoimmune encephalomyelitis (EAE) model binds in a conventional orientation, but the structure is unusual because the self-peptide only partially fills the binding site. For all three TCRs, interaction with the MHC bound self-peptide is suboptimal, and only two or three TCR loops contact the peptide. Optimal TCR binding modes confer a competitive advantage for antimicrobial T cells during an infection, whereas altered binding properties may permit survival of a subset of autoreactive T cells during thymic selection. Autoimmune diseases are caused by self-reactive T cells that have escaped negative selection during T cell development in the thymus (Goodnow et al., 2005Goodnow C.C. Sprent J. de St Groth B.F. Vinuesa C.G. Cellular and genetic mechanisms of self tolerance and autoimmunity.Nature. 2005; 435: 590-597Crossref PubMed Scopus (496) Google Scholar). In many autoimmune diseases, pathogenic T cells recognize “tissue-specific” antigens, and it was previously thought that the presence of such autoreactive T cells is due to a lack of self-antigen expression in the thymus. However, more recent work has convincingly demonstrated that most tissue-specific self-antigens are in fact expressed in the thymus by an unusual subpopulation of medullary thymic epithelial cells (mTECs) that express a wide range of tissue-specific genes in a promiscuous manner (Derbinski et al., 2001Derbinski J. Schulte A. Kyewski B. Klein L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self.Nat. Immunol. 2001; 2: 1032-1039Crossref PubMed Scopus (2) Google Scholar). The expressed genes encode autoantigens relevant in human autoimmune diseases; such autoantigens include myelin basic protein (MBP) and proteolipid protein (PLP), which are considered to be target antigens in multiple sclerosis (MS) (Pribyl et al., 1996Pribyl T.M. Campagnoni C. Kampf K. Handley V.W. Campagnoni A.T. The major myelin protein genes are expressed in the human thymus.J. Neurosci. Res. 1996; 45: 812-819Crossref Scopus (90) Google Scholar, Derbinski et al., 2001Derbinski J. Schulte A. Kyewski B. Klein L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self.Nat. Immunol. 2001; 2: 1032-1039Crossref PubMed Scopus (2) Google Scholar). The promiscuous expression of these genes in mTECs is in part controlled by the transcription factor AIRE, and both humans (The Finnish-German APECED Consortium, 1997The Finnish-German APECED ConsortiumAn autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains.Nat. Genet. 1997; 17: 399-403Crossref PubMed Scopus (931) Google Scholar) and mice with a defective AIRE gene (Anderson et al., 2002Anderson M.S. Venanzi E.S. Klein L. Chen Z. Berzins S.P. Turley S.J. von Boehmer H. Bronson R. Dierich A. Benoist C. Mathis D. Projection of an immunological self shadow within the thymus by the aire protein.Science. 2002; 298: 1395-1401Crossref PubMed Scopus (1757) Google Scholar) develop autoimmunity in multiple organs. Several explanations for a failure of negative selection have been proposed on the basis of experiments in animal models of autoimmunity. Particularly instructive has been a comparison of the T cell response to a self-antigen between wild-type and knockout mice that lack expression of the self-antigen in question. Collectively, these experiments have demonstrated that expression of the self-antigen has striking effects on the T cell repertoire and that T cells directed against certain epitopes are largely deleted, whereas T cells that recognize other epitopes escape negative selection (Harrington et al., 1998Harrington C.J. Paez A. Hunkapiller T. Mannikko V. Brabb T. Ahearn M. Beeson C. Goverman J. Differential tolerance is induced in T cells recognizing distinct epitopes of myelin basic protein.Immunity. 1998; 8: 571-580Abstract Full Text Full Text PDF Scopus (165) Google Scholar, Klein et al., 2000Klein L. Klugmann M. Nave K.A. Tuohy V.K. Kyewski B. Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells.Nat. Med. 2000; 6: 56-61Crossref PubMed Scopus (313) Google Scholar). Comparison of the CD4 T cell response in MBP-deficient and wild-type H-2u mice showed that the response to MBP is far more vigorous in MBP-deficient mice and that the majority of responding T cells in MBP-deficient mice recognize the 121–150 region of MBP (Harrington et al., 1998Harrington C.J. Paez A. Hunkapiller T. Mannikko V. Brabb T. Ahearn M. Beeson C. Goverman J. Differential tolerance is induced in T cells recognizing distinct epitopes of myelin basic protein.Immunity. 1998; 8: 571-580Abstract Full Text Full Text PDF Scopus (165) Google Scholar). In contrast, the CD4 T cell response in wild-type H-2u mice is primarily focused on the N-terminal Ac1-11 epitope of MBP that binds with low affinity to I-Au, whereas a T cell response to the high-affinity 121–150 peptide is barely detectable (Zamvil et al., 1986Zamvil S.S. Mitchell D.J. Moore A.C. Kitamura K. Steinman L. Rothbard J.B. T-cell epitope of the autoantigen myelin basic protein that induces encephalomyelitis.Nature. 1986; 324: 258-260Crossref PubMed Scopus (396) Google Scholar, Harrington et al., 1998Harrington C.J. Paez A. Hunkapiller T. Mannikko V. Brabb T. Ahearn M. Beeson C. Goverman J. Differential tolerance is induced in T cells recognizing distinct epitopes of myelin basic protein.Immunity. 1998; 8: 571-580Abstract Full Text Full Text PDF Scopus (165) Google Scholar). Alternative splicing has been implicated as another mechanism for a failure of negative selection in another EAE model in which the T cell response is primarily focused on an epitope of PLP. The PLP splice variant present in the thymus lacks the critical T cell epitope, resulting in a selective defect of thymic negative selection to the PLP 139–151 peptide (Anderson et al., 2000Anderson A.C. Nicholson L.B. Legge K.L. Turchin V. Zaghouani H. Kuchroo V.K. High frequency of autoreactive myelin proteolipid protein-specific T cells in the periphery of naive mice: Mechanisms of selection of the self-reactive repertoire.J. Exp. Med. 2000; 191: 761-770Crossref PubMed Scopus (237) Google Scholar, Klein et al., 2000Klein L. Klugmann M. Nave K.A. Tuohy V.K. Kyewski B. Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells.Nat. Med. 2000; 6: 56-61Crossref PubMed Scopus (313) Google Scholar). These two mechanisms—low-affinity peptide binding and alternative splicing—do not account for the majority of cases in which autoreactive T cells are present in the mature T cell repertoire. A substantial number of peptides that are recognized by self-reactive T cells bind with an intermediate or high affinity to the relevant MHC molecule (Wall et al., 1992Wall M. Southwood S. Sidney J. Oseroff C. del Guericio M.F. Lamont A.G. Colon S.M. Arrhenius T. Gaeta F.C. Sette A. High affinity for class II molecules as a necessary but not sufficient characteristic of encephalitogenic determinants.Int. Immunol. 1992; 4: 773-777Crossref Scopus (43) Google Scholar, Valli et al., 1993Valli A. Sette A. Kappos L. Oseroff C. Sidney J. Miescher G. Hochberger M. Albert E.D. Adorini L. Binding of myelin basic protein peptides to human histocompatibility leukocyte antigen class II molecules and their recognition by T cells from multiple sclerosis patients.J. Clin. Invest. 1993; 91: 616-628Crossref Scopus (192) Google Scholar, Wucherpfennig et al., 1994aWucherpfennig K.W. Sette A. Southwood S. Oseroff C. Matsui M. Strominger J.L. Hafler D.A. Structural requirements for binding of an immunodominant myelin basic protein peptide to DR2 isotypes and for its recognition by human T cell clones.J. Exp. Med. 1994; 179: 279-290Crossref Scopus (311) Google Scholar), and in most cases the relevant antigen and the epitope in question are expressed in the thymus (Pribyl et al., 1996Pribyl T.M. Campagnoni C. Kampf K. Handley V.W. Campagnoni A.T. The major myelin protein genes are expressed in the human thymus.J. Neurosci. Res. 1996; 45: 812-819Crossref Scopus (90) Google Scholar, Derbinski et al., 2001Derbinski J. Schulte A. Kyewski B. Klein L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self.Nat. Immunol. 2001; 2: 1032-1039Crossref PubMed Scopus (2) Google Scholar). Two recent studies have indicated that general alterations in T cell signaling thresholds can profoundly affect the outcome of thymic selection events. The molecular defects can affect either early TCR signaling events or more distal signaling pathways that initiate apoptosis in thymocytes (Sakaguchi et al., 2003Sakaguchi N. Takahashi T. Hata H. Nomura T. Tagami T. Yamazaki S. Sakihama T. Matsutani T. Negishi I. Nakatsuru S. Sakaguchi S. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice.Nature. 2003; 426: 454-460Crossref PubMed Scopus (606) Google Scholar, Liston et al., 2004Liston A. Lesage S. Gray D.H. O’Reilly L.A. Strasser A. Fahrer A.M. Boyd R.L. Wilson J. Baxter A.G. Gallo E.M. et al.Generalized resistance to thymic deletion in the NOD mouse: A polygenic trait characterized by defective induction of Bim.Immunity. 2004; 21: 817-830Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). In a spontaneously occurring mouse model of rheumatoid arthritis (SKG mice), the genetic defect was pinpointed to the SH2 domain of ZAP-70, a tyrosine kinase that associates with the ζ chain of the TCR-CD3 complex (Sakaguchi et al., 2003Sakaguchi N. Takahashi T. Hata H. Nomura T. Tagami T. Yamazaki S. Sakihama T. Matsutani T. Negishi I. Nakatsuru S. Sakaguchi S. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice.Nature. 2003; 426: 454-460Crossref PubMed Scopus (606) Google Scholar). Diminished TCR signaling dramatically affected thymic selection and resulted in positive selection of otherwise negatively selected autoreactive T cells (Sakaguchi et al., 2003Sakaguchi N. Takahashi T. Hata H. Nomura T. Tagami T. Yamazaki S. Sakihama T. Matsutani T. Negishi I. Nakatsuru S. Sakaguchi S. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice.Nature. 2003; 426: 454-460Crossref PubMed Scopus (606) Google Scholar). It is possible that alterations in TCR binding to peptide/MHC, which modulate the strength of TCR signaling in the thymus, can lead to a similar outcome. The first crystal structures of TCR/peptide/MHC class I complexes showed remarkable similarities in the overall topology of TCR binding to peptide/MHC, even though the TCRs originated from two different species and had been isolated from distinct biological settings, a chronic infectious disease (human A6 TCR), and an alloimmune response (murine 2C TCR) (Garboczi et al., 1996Garboczi D.N. Ghosh P. Utz U. Fan Q.R. Biddison W.E. Wiley D.C. Structure of the complex between human T-cell receptor, viral peptide and HLA-A2.Nature. 1996; 384: 134-141Crossref PubMed Scopus (1173) Google Scholar, Garcia et al., 1996Garcia K.C. Degano M. Stanfield R.L. Brunmark A. Jackson M.R. Peterson P.A. Teyton L. Wilson I.A. An αβ T cell receptor structure at 2.5 Å and its orientation in the TCR-MHC complex.Science. 1996; 274: 209-219Crossref PubMed Scopus (1033) Google Scholar, Garcia et al., 1998Garcia K.C. Degano M. Pease L.R. Huang M. Peterson P.A. Teyton L. Wilson I.A. Structural basis of plasticity in T cell receptor recognition of a self peptide-MHC antigen.Science. 1998; 279: 1166-1172Crossref PubMed Scopus (580) Google Scholar). In both structures, the TCR is positioned diagonally across the compound surface created by the peptide and the long MHC helices that flank the peptide binding site such that the TCR covers most of the MHC bound peptide (illustrated for A6 TCR in Figures 1A and 1B ). The most diverse TCR loops, the CDR3 loops of TCRα and β chains, are located over the central peptide residue and form a pocket that accommodates this peptide side chain (P5 tyrosine of the nine amino acid Tax peptide in the A6 structure, Figures 1B–1D). This TCR position permits extensive interactions between the most diverse TCR loops and the central segment of the MHC bound peptide. The other TCR loops (CDR1 and CDR2) are encoded by the V gene segments and are less diverse in sequence among different TCRs. The diagonal orientation places the CDR1 loops of TCRα and TCRβ over the N-terminal and C-terminal segments of MHC class I bound peptides (Figure 1C), such that a total of four TCR loops (CDR1 and CDR3 loops of both chains) can participate in peptide recognition. The CDR1 loops can also contact the MHC helices. In contrast, the CDR2 loops of both chains are positioned over the MHC helices and do not participate in peptide recognition in these structures (Figure 1C) (Garcia et al., 1999Garcia K.C. Teyton L. Wilson I.A. Structural basis of T cell recognition.Annu. Rev. Immunol. 1999; 17: 369-397Crossref Scopus (401) Google Scholar, Hennecke and Wiley, 2001Hennecke J. Wiley D.C. T cell receptor-MHC interactions up close.Cell. 2001; 104: 1-4Abstract Full Text Full Text PDF Scopus (142) Google Scholar, Rudolph and Wilson, 2002Rudolph M.G. Wilson I.A. The specificity of TCR/pMHC interaction.Curr. Opin. Immunol. 2002; 14: 52-65Crossref PubMed Scopus (237) Google Scholar). The TCR surface that contacts peptide/MHC was found to be rather flat, with the exception of the central cavity described above. In contrast, the MHC helices form two high points at opposite ends, and the TCR avoids these high points by a diagonal orientation (Figure 1B). Subsequent MHC class I/peptide/TCR structures enforced the view that this binding topology may be general and led to the hypothesis that the germline-encoded CDR1 and CDR2 loops have evolved to recognize structural features of MHC molecules (Ding et al., 1998Ding Y.H. Smith K.J. Garboczi D.N. Utz U. Biddison W.E. Wiley D.C. Two human T cell receptors bind in a similar diagonal mode to the HLA-A2/Tax peptide complex using different TCR amino acids.Immunity. 1998; 8: 403-411Abstract Full Text Full Text PDF Scopus (388) Google Scholar, Garcia et al., 1999Garcia K.C. Teyton L. Wilson I.A. Structural basis of T cell recognition.Annu. Rev. Immunol. 1999; 17: 369-397Crossref Scopus (401) Google Scholar, Reiser et al., 2000Reiser J.B. Darnault C. Guimezanes A. Gregoire C. Mosser T. Schmitt-Verhulst A.M. Fontecilla-Camps J.C. Malissen B. Housset D. Mazza G. Crystal structure of a T cell receptor bound to an allogeneic MHC molecule.Nat. Immunol. 2000; 1: 291-297Crossref Scopus (183) Google Scholar, Reiser et al., 2002Reiser J.B. Gregoire C. Darnault C. Mosser T. Guimezanes A. Schmitt-Verhulst A.M. Fontecilla-Camps J.C. Mazza G. Malissen B. Housset D. A T cell receptor CDR3β loop undergoes conformational changes of unprecedented magnitude upon binding to a peptide/MHC class I complex.Immunity. 2002; 16: 345-354Abstract Full Text Full Text PDF Scopus (177) Google Scholar, Reiser et al., 2003Reiser J.B. Darnault C. Gregoire C. Mosser T. Mazza G. Kearney A. van der Merwe P.A. Fontecilla-Camps J.C. Housset D. Malissen B. CDR3 loop flexibility contributes to the degeneracy of TCR recognition.Nat. Immunol. 2003; 4: 241-247Crossref PubMed Scopus (197) Google Scholar, Hennecke and Wiley, 2001Hennecke J. Wiley D.C. T cell receptor-MHC interactions up close.Cell. 2001; 104: 1-4Abstract Full Text Full Text PDF Scopus (142) Google Scholar, Rudolph and Wilson, 2002Rudolph M.G. Wilson I.A. The specificity of TCR/pMHC interaction.Curr. Opin. Immunol. 2002; 14: 52-65Crossref PubMed Scopus (237) Google Scholar, Stewart-Jones et al., 2003Stewart-Jones G.B. McMichael A.J. Bell J.I. Stuart D.I. Jones E.Y. A structural basis for immunodominant human T cell receptor recognition.Nat. Immunol. 2003; 4: 657-663Crossref Scopus (245) Google Scholar). A contribution of the CDR1 or CDR2 loop of TCRα to MHC binding was shown by experiments in which single amino acid substitutions in these TCR loops affected T cell differentiation to the CD4 or CD8 lineage (Sim et al., 1996Sim B.C. Zerva L. Greene M.I. Gascoigne N.R. Control of MHC restriction by TCR Vα CDR1 and CDR2.Science. 1996; 273: 963-966Crossref Scopus (137) Google Scholar). However, mutagenesis experiments failed to identify conserved MHC side chains required for recognition by all TCRs (Sun et al., 1995Sun R. Shepherd S.E. Geier S.S. Thomson C.T. Sheil J.M. Nathenson S.G. Evidence that the antigen receptors of cytotoxic T lymphocytes interact with a common recognition pattern on the H-2Kb molecule.Immunity. 1995; 3: 573-582Abstract Full Text PDF Scopus (85) Google Scholar, Baker et al., 2001Baker B.M. Turner R.V. Gagnon S.J. Wiley D.C. Biddison W.E. Identification of a crucial energetic footprint on the alpha1 helix of human histocompatibility leukocyte antigen (HLA)-A2 that provides functional interactions for recognition by tax peptide/HLA-A2-specific T cell receptors.J. Exp. Med. 2001; 193: 551-562Crossref Scopus (74) Google Scholar). Subsequently, the structures of two MHC class II restricted TCRs were determined that recognize foreign peptides: the mouse D10 TCR specific for a conalbumin peptide bound to I-Ak (Reinherz et al., 1999Reinherz E.L. Tan K. Tang L. Kern P. Liu J. Xiong Y. Hussey R.E. Smolyar A. Hare B. Zhang R. et al.The crystal structure of a T cell receptor in complex with peptide and MHC class II.Science. 1999; 286: 1913-1921Crossref PubMed Scopus (352) Google Scholar), and the human HA1.7 TCR specific for an influenza hemagglutinin (HA, residues 306–318) peptide bound to HLA-DR1 (DRA, DRB1*0101) (Figure 2A ; Table 1) (Hennecke et al., 2000Hennecke J. Carfi A. Wiley D.C. Structure of a covalently stabilized complex of a human αβ T-cell receptor, influenza HA peptide and MHC class II molecule, HLA-DR1.EMBO J. 2000; 19: 5611-5624Crossref Google Scholar). In contrast to MHC class I molecules, the peptide binding site of MHC class II molecules is open at both ends, permitting binding of longer peptides (Brown et al., 1993Brown J.H. Jardetzky T.S. Gorga J.C. Stern L.J. Urban R.G. Strominger J.L. Wiley D.C. Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1.Nature. 1993; 364: 33-39Crossref PubMed Scopus (2055) Google Scholar). Despite these differences between MHC class I and class II molecules, both of these MHC class II restricted TCRs bind with a very similar topology as the MHC class I restricted TCRs described above. The only substantial difference between MHC class I and class II restricted TCRs appeared to be the crossing angle (defined by a line drawn through the peptide and a line through the centers of mass of the TCR variable domains) because the first structure of an MHC class II restricted TCR (D10 TCR) (Reinherz et al., 1999Reinherz E.L. Tan K. Tang L. Kern P. Liu J. Xiong Y. Hussey R.E. Smolyar A. Hare B. Zhang R. et al.The crystal structure of a T cell receptor in complex with peptide and MHC class II.Science. 1999; 286: 1913-1921Crossref PubMed Scopus (352) Google Scholar) suggested a more orthogonal position (80°) than previously reported structures for MHC class I restricted T cells (45°–70°) (Garcia et al., 1999Garcia K.C. Teyton L. Wilson I.A. Structural basis of T cell recognition.Annu. Rev. Immunol. 1999; 17: 369-397Crossref Scopus (401) Google Scholar). However, subsequent studies demonstrated that there are no global differences in the binding angle between MHC class I and class II restricted TCRs (Hennecke and Wiley, 2001Hennecke J. Wiley D.C. T cell receptor-MHC interactions up close.Cell. 2001; 104: 1-4Abstract Full Text Full Text PDF Scopus (142) Google Scholar, Rudolph and Wilson, 2002Rudolph M.G. Wilson I.A. The specificity of TCR/pMHC interaction.Curr. Opin. Immunol. 2002; 14: 52-65Crossref PubMed Scopus (237) Google Scholar, Stewart-Jones et al., 2003Stewart-Jones G.B. McMichael A.J. Bell J.I. Stuart D.I. Jones E.Y. A structural basis for immunodominant human T cell receptor recognition.Nat. Immunol. 2003; 4: 657-663Crossref Scopus (245) Google Scholar). The overall similarities between these initial structures of MHC class I and class II TCR complexes further enforced the notion that all TCRs bind to peptide/MHC complexes in a similar fashion. All human TCRs analyzed in these studies recognized viral peptides, and the T cell clones from which they had been isolated represented predominant T cell populations in the immune response to the virus. In vivo competition (Kedl et al., 2003Kedl R.M. Kappler J.W. Marrack P. Epitope dominance, competition and T cell affinity maturation.Curr. Opin. Immunol. 2003; 15: 120-127Crossref Scopus (186) Google Scholar) may therefore have resulted in the expansion of T cells whose TCRs have optimal binding properties for these viral peptide/MHC ligands.Table 1MHC Class II Restricted TCRs for which the Structure of TCR/Peptide/MHC Complex Has Been DeterminedTCRPeptideMHC Class IISpeciesTCRs Specific for Foreign PeptidesHA1.7Influenza hemagglutinin, 306–318DRA, DRB1*0101HumanD10Conalbumin, 131–144I-AkMouseTCRs Specific for Self PeptidesOb.1A12Human myelin basic protein, 85–99DRA, DRB1*1501Human3A6Human myelin basic protein, 89–101DRA, DRB5*0101Human172.10Mouse myelin basic protein, Ac1–11I-AuMouseThe HA1.7 and D10 TCRs are specific for foreign peptides, whereas the human Ob.1A12 and 3A6 TCRs as well as the murine 172.10 TCR recognize different epitopes of the self-antigen myelin basic protein. Open table in a new tab The HA1.7 and D10 TCRs are specific for foreign peptides, whereas the human Ob.1A12 and 3A6 TCRs as well as the murine 172.10 TCR recognize different epitopes of the self-antigen myelin basic protein. The first crystal structure of a human autoimmune TCR (Ob.1A12 TCR) bound to its self-peptide/MHC ligand showed a strikingly different topology (Figure 2C) (Hahn et al., 2005Hahn M. Nicholson M.J. Pyrdol J. Wucherpfennig K.W. Unconventional topology of self peptide-major histocompatibility complex binding by a human autoimmune T cell receptor.Nat. Immunol. 2005; 6: 490-496Crossref Scopus (202) Google Scholar), which was surprising given the strong similarities between all of the previously reported TCR/peptide/MHC structures. The Ob.1A12 TCR originated from a patient with relapsing-remitting MS and is specific for a major epitope of human MBP (residues 85–99) bound to a MS-associated MHC class II molecule (DRA, DRB1*1501) (Ota et al., 1990Ota K. Matsui M. Milford E.L. Mackin G.A. Weiner H.L. Hafler D.A. T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis.Nature. 1990; 346: 183-187Crossref PubMed Scopus (778) Google Scholar, Wucherpfennig et al., 1994aWucherpfennig K.W. Sette A. Southwood S. Oseroff C. Matsui M. Strominger J.L. Hafler D.A. Structural requirements for binding of an immunodominant myelin basic protein peptide to DR2 isotypes and for its recognition by human T cell clones.J. Exp. Med. 1994; 179: 279-290Crossref Scopus (311) Google Scholar). Transgenic mice that express this human TCR and the MHC class II molecule develop a spontaneous inflammatory disease in the CNS that has similarities with the human disease, demonstrating that this TCR has the potential to be pathogenic in vivo (Madsen et al., 1999Madsen L.S. Andersson E.C. Jansson L. Krogsgaard M. Andersen C.B. Engberg J. Strominger J.L. Svejgaard A. Hjorth J.P. Holmdahl R. et al.A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor.Nat. Genet. 1999; 23: 343-347Crossref Scopus (286) Google Scholar, Ellmerich et al., 2004Ellmerich S. Takacs K. Mycko M. Waldner H. Wahid F. Boyton R.J. Smith P.A. Amor S. Baker D. Hafler D.A. et al.Disease-related epitope spread in a humanized T cell receptor transgenic model of multiple sclerosis.Eur. J. Immunol. 2004; 34: 1839-1848Crossref PubMed Scopus (44) Google Scholar). The structure showed that the Ob.1A12 TCR is not centered over the peptide/MHC surface and that it only contacts the N-terminal segment of the peptide (Figure 2C). In addition, the TCR does not make symmetrical interactions with the MHC helices, but is shifted and tilted toward the DRβ chain helix. Another unusual feature is the counterclockwise rotation of Ob.1A12 TCR relative to the MHC molecule when compared to HA1.7 TCR. The crossing angle is 70° for HA1.7 TCR, within the 45°–80° range observed for other TCRs, but 110° for Ob.1A12 TCR. This altered position of the TCR dramatically affects peptide recognition. This is particularly evident in the position of the two CDR3 loops, which create a large cavity over the P2 side chain, rather than the P5 side chain (Figure 3, Figure 4, Figure 5, left panel). The lateral shift in the location of the CDR3 loops is substantial and corresponds to three peptide residues. The cavity created by the CDR3 loops not only accommodates a peptide side chain (P2 histidine, Figure 3C), but also a side chain from a MHC helix (DRβ81 histidine, Figure 5C, left panel).Figure 4Peptide Contacts Established by TCR CDR3 Loops in Human and Murine TCR/Peptide/MHC Class II StructuresShow full captionThe peptide residues that occupy the P1, P4, P6, and P9 pockets of the MHC class II peptide binding site are colored light blue in all five peptide sequences. Peptide residues contacted by CDR3 loops are colored orange, and contacts to CDR3α or CDR3β are indicated by shaded areas. Contacts that represent hydrogen bonds are marked with a dotted line, which is colored red when the contact involves a side chain of the peptide.In the HA1.7 (human) and D10 (mouse) structures in which the TCR recognizes a foreign peptide, both CDR3 loops are located over the center of the peptide. In contrast, both human autoimmune TCRs (Ob.1A12 and 3A6) are characterized by a shift of the CDR3 loops toward the N terminus of the peptide. The mouse 172.10 TCR recognizes the N-terminal MBP Ac1-11 peptide that only partially fills the peptide binding site. This structure also contains a peptide extension by the insect leader peptide, which is not part of the native MBP peptide and thus not included in this figure. The CDR3 loops of D10 TCR do not form hydrogen bonds to the peptide, but a hydrogen bond is present between the CDR1α loop and P2 arginine of the peptide.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 5Location of the TCR Loops on the Peptide/MHC Surface in the Three Human TCR/Peptide/MHC Class II StructuresShow full captionIn the left panel, the CDR3 loops are located over the center of the peptide/MHC surface in the HA1.7 structure, but are shifted toward the peptide N terminus in the 3A6 and Ob.1A12 structures. The CDR3α (yellow) and CDR3β (red) loops are labeled as α3 and β3, respectively. Residues involved in hydrogen bonds are represented as small spheres.In the right panel, the CDR1 and CDR2 loops of TCRβ chains are located in different positions in each of the three structures, and their position is most extreme in the Ob.1A12 structure. The position of the CDR1 and CDR2 loops of TCRα chains is more similar among the three structures, but the CDR2α loop of 3A6 TCR fails to contact peptide/MHC. The CDR1 and CDR2 loops of TCRα and β are labeled as α1, α2, β1, and β2. The figure was prepared with Deep View/Swiss-PDB Viewer (Guex and Peitsch, 1997Guex N. Peitsch M.C. SWISS-MODEL and the Swiss-PdbViewer: An environment for comparative protein modeling.Electrophoresis. 1997; 18: 2714-2723Crossref PubMed Scopus (9111) Google Scholar) and POV-Ray (http://www2.povray.org/).View Large Image Figure ViewerDownload Hi-res image Download (PPT) The peptide residues that occupy the P1, P4, P6, and P9 pockets of the MHC class II peptide binding site are colored light blue in all five peptide sequences. Peptide residues contacted by CDR3 loops are color" @default.
• W2056315052 created "2016-06-24" @default.
• W2056315052 creator A5006962892 @default.
• W2056315052 creator A5030650949 @default.
• W2056315052 creator A5084053909 @default.
• W2056315052 date "2005-10-01" @default.
• W2056315052 modified "2023-10-17" @default.
• W2056315052 title "Unusual Features of Self-Peptide/MHC Binding by Autoimmune T Cell Receptors" @default.
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