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• W2146652028 abstract "T cells often alloreact with foreign human leukocyte antigens (HLA). Here we showed the LC13 T cell receptor (TCR), selected for recognition on self-HLA-B∗0801 bound to a viral peptide, alloreacts with B44 allotypes (HLA-B∗4402 and HLA-B∗4405) bound to two different allopeptides. Despite extensive polymorphism between HLA-B∗0801, HLA-B∗4402, and HLA-B∗4405 and the disparate sequences of the viral and allopeptides, the LC13 TCR engaged these peptide-HLA (pHLA) complexes identically, accommodating mimicry of the viral peptide by the allopeptide. The viral and allopeptides adopted similar conformations only after TCR ligation, revealing an induced-fit mechanism of molecular mimicry. The LC13 T cells did not alloreact against HLA-B∗4403, and the single residue polymorphism between HLA-B∗4402 and HLA-B∗4403 affected the plasticity of the allopeptide, revealing that molecular mimicry was associated with TCR specificity. Accordingly, molecular mimicry that is HLA and peptide dependent is a mechanism for human T cell alloreactivity between disparate cognate and allogeneic pHLA complexes. T cells often alloreact with foreign human leukocyte antigens (HLA). Here we showed the LC13 T cell receptor (TCR), selected for recognition on self-HLA-B∗0801 bound to a viral peptide, alloreacts with B44 allotypes (HLA-B∗4402 and HLA-B∗4405) bound to two different allopeptides. Despite extensive polymorphism between HLA-B∗0801, HLA-B∗4402, and HLA-B∗4405 and the disparate sequences of the viral and allopeptides, the LC13 TCR engaged these peptide-HLA (pHLA) complexes identically, accommodating mimicry of the viral peptide by the allopeptide. The viral and allopeptides adopted similar conformations only after TCR ligation, revealing an induced-fit mechanism of molecular mimicry. The LC13 T cells did not alloreact against HLA-B∗4403, and the single residue polymorphism between HLA-B∗4402 and HLA-B∗4403 affected the plasticity of the allopeptide, revealing that molecular mimicry was associated with TCR specificity. Accordingly, molecular mimicry that is HLA and peptide dependent is a mechanism for human T cell alloreactivity between disparate cognate and allogeneic pHLA complexes. Clonally distributed αβ T cell receptors (TCR) corecognize specific antigenic peptides bound to polymorphic human leukocyte antigens (HLA) of the major histocompatibility complex (MHC) (Davis et al., 1998Davis M.M. Boniface J.J. Reich Z. Lyons D. Hampl J. Arden B. Chien Y. Ligand recognition by alpha beta T cell receptors.Annu. Rev. Immunol. 1998; 16: 523-544Crossref PubMed Scopus (745) Google Scholar, Rudolph et al., 2006Rudolph M.G. Stanfield R.L. Wilson I.A. How TCRs bind MHCs, peptides, and coreceptors.Annu. Rev. Immunol. 2006; 24: 419-466Crossref PubMed Scopus (828) Google Scholar). HLA polymorphism ensures that the HLA molecules from different haplotypes can bind a broad sample of self and microbial peptide antigens necessary to mediate adaptive immunity (Parham and Ohta, 1996Parham P. Ohta T. Population biology of antigen presentation by MHC class I molecules.Science. 1996; 272: 67-74Crossref PubMed Scopus (511) Google Scholar). Developing T cells in the thymus are selected for weak recognition of one or more of the many self-peptide-HLA complexes (Bevan and Hünig, 1981Bevan M.J. Hünig T. T cells respond preferentially to antigens that are similar to self H-2.Proc. Natl. Acad. Sci. USA. 1981; 78: 1843-1847Crossref PubMed Scopus (28) Google Scholar, Hogquist et al., 1993Hogquist K.A. Gavin M.A. Bevan M.J. Positive selection of CD8+ T cells induced by major histocompatibility complex binding peptides in fetal thymic organ culture.J. Exp. Med. 1993; 177: 1469-1473Crossref PubMed Scopus (209) Google Scholar) generating a large repertoire of T cells, each expressing individual TCRs (Fink and Bevan, 1995Fink P.J. Bevan M.J. Positive selection of thymocytes.Adv. Immunol. 1995; 59: 99-133Crossref PubMed Scopus (94) Google Scholar). Inherent structural plasticity of the TCR contributes to chance improvements in recognition of novel peptide-HLA complexes (pHLA) that are generated when self-peptides are replaced with foreign peptides during infection (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, Garcia et al., 1999Garcia K.C. Degano M. Speir J.A. Wilson I.A. Emerging principles for T cell receptor recognition of antigen in cellular immunity.Rev. Immunogenet. 1999; 1: 75-90PubMed Google Scholar, Rudolph et al., 2006Rudolph M.G. Stanfield R.L. Wilson I.A. How TCRs bind MHCs, peptides, and coreceptors.Annu. Rev. Immunol. 2006; 24: 419-466Crossref PubMed Scopus (828) Google Scholar). This recognition triggers effector immunity by responsive T cells. Despite pHLA diversity and TCR plasticity, αβ-T cell responses remain exquisitely specific (Archbold et al., 2009Archbold J.K. Macdonald W.A. Gras S. Ely L.K. Miles J.J. Bell M.J. Brennan R.M. Beddoe T. Wilce M.C.J. Clements C.S. et al.Natural micropolymorphism in human leukocyte antigens provides a basis for genetic control of antigen recognition.J. Exp. Med. 2009; 206: 209-219Crossref PubMed Scopus (76) Google Scholar) and are developmentally restricted to recognizing host (self) HLA (Jameson et al., 1995Jameson S.C. Hogquist K.A. Bevan M.J. Positive selection of thymocytes.Annu. Rev. Immunol. 1995; 13: 93-126Crossref PubMed Scopus (531) Google Scholar, Zinkernagel and Doherty, 1974Zinkernagel R.M. Doherty P.C. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system.Nature. 1974; 248: 701-702Crossref PubMed Scopus (1387) Google Scholar), with the exception of minor subpopulations like NKT cells (Borg et al., 2007Borg N.A. Wun K.S. Kjer-Nielsen L. Wilce M.C. Pellicci D.G. Koh R. Besra G.S. Bharadwaj M. Godfrey D.I. McCluskey J. Rossjohn J. CD1d-lipid-antigen recognition by the semi-invariant NKT T-cell receptor.Nature. 2007; 448: 44-49Crossref PubMed Scopus (456) Google Scholar). This “genetic restriction” of MHC-directed T cell immunity means that T cells recognize only cognate antigen presented by one of the host HLA molecules in which they developed (also termed MHC restriction) (Zinkernagel and Doherty, 1974Zinkernagel R.M. Doherty P.C. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system.Nature. 1974; 248: 701-702Crossref PubMed Scopus (1387) Google Scholar). This “law” of immunology is a defining paradigm of antigen-specific T cell immunity (Garboczi and Biddison, 1999Garboczi D.N. Biddison W.E. Shapes of MHC restriction.Immunity. 1999; 10: 1-7Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). Surprisingly, some T cells break the “law” of MHC restriction (Sherman and Chattopadhyay, 1993Sherman L.A. Chattopadhyay S. The molecular basis of allorecognition.Annu. Rev. Immunol. 1993; 11: 385-402Crossref PubMed Scopus (357) Google Scholar) by directly reacting with “foreign” HLA molecules from unrelated (allogeneic) individuals. HLA polymorphism involving just one amino acid, or up to 30 or more residues, can induce an immune response toward transplanted cells, the severity of which is variable. Thus, some HLA mismatches lead to worse transplant outcomes than others, so-called taboo mismatches (Doxiadis et al., 1996Doxiadis I.I. Smits J.M. Schreuder G.M. Persijn G.G. van Houwelingen H.C. van Rood J.J. Claas F.H. Association between specific HLA combinations and probability of kidney allograft loss: The taboo concept.Lancet. 1996; 348: 850-853Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, Kawase et al., 2007Kawase T. Morishima Y. Matsuo K. Kashiwase K. Inoko H. Saji H. Kato S. Juji T. Kodera Y. Sasazuki T. Japan Marrow Donor ProgramHigh-risk HLA allele mismatch combinations responsible for severe acute graft-versus-host disease and implication for its molecular mechanism.Blood. 2007; 110: 2235-2241Crossref PubMed Scopus (211) Google Scholar). For instance, mismatching across closely related HLA allotypes such as HLA-B∗4402 and HLA-B∗4403 provokes vigorous T cell alloreactivity (Mifsud et al., 2008Mifsud N.A. Purcell A.W. Chen W. Holdsworth R. Tait B.D. McCluskey J. Immunodominance hierarchies and gender bias in direct T(CD8)-cell alloreactivity.Am. J. Transplant. 2008; 8: 121-132Crossref PubMed Scopus (27) Google Scholar) associated with transplant rejection (Fleischhauer et al., 1990Fleischhauer K. Kernan N.A. O'Reilly R.J. Dupont B. Yang S.Y. Bone marrow-allograft rejection by T lymphocytes recognizing a single amino acid difference in HLA-B44.N. Engl. J. Med. 1990; 323: 1818-1822Crossref PubMed Scopus (288) Google Scholar) and acute graft-versus-host disease (Keever et al., 1994Keever C.A. Leong N. Cunningham I. Copelan E.A. Avalos B.R. Klein J. Kapoor N. Adams P.W. Orosz C.G. Tutschka P.J. et al.HLA-B44-directed cytotoxic T cells associated with acute graft-versus-host disease following unrelated bone marrow transplantation.Bone Marrow Transplant. 1994; 14: 137-145PubMed Google Scholar) after haemopoietic stem cell transplantation, despite the broadly similar peptide repertoires of these allotypes (Macdonald et al., 2003Macdonald W.A. Purcell A.W. Mifsud N.A. Ely L.K. Williams D.S. Chang L. Gorman J.J. Clements C.S. Kjer-Nielsen L. Koelle D.M. et al.A naturally selected dimorphism within the HLA-B44 supertype alters class I structure, peptide repertoire, and T cell recognition.J. Exp. Med. 2003; 198: 679-691Crossref PubMed Scopus (166) Google Scholar). In contrast, highly divergent HLA mismatches may paradoxically have a better outcome in some transplant settings (Heemskerk et al., 2007Heemskerk M.B. Cornelissen J.J. Roelen D.L. van Rood J.J. Claas F.H. Doxiadis I.I. Oudshoorn M. Highly diverged MHC class I mismatches are acceptable for haematopoietic stem cell transplantation.Bone Marrow Transplant. 2007; 40: 193-200Crossref PubMed Scopus (39) Google Scholar). Regardless, T cell alloreactivity is responsible for much of the morbidity and mortality associated with tissue transplantation, including graft-versus-host disease (Afzali et al., 2007Afzali B. Lechler R.I. Hernandez-Fuentes M.P. Allorecognition and the alloresponse: clinical implications.Tissue Antigens. 2007; 69: 545-556Crossref PubMed Scopus (104) Google Scholar), making this unexplained contradiction to the phenomenon of MHC restriction of great clinical importance. The paradox of alloreactivity has remained a mystery for more than three decades (Archbold et al., 2008bArchbold J.K. Macdonald W.A. Burrows S.R. Rossjohn J. McCluskey J. T-cell allorecognition: A case of mistaken identity or déjà vu?.Trends Immunol. 2008; 29: 220-226Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, Dröge, 1979Dröge W. Hypothesis on the origin of the strong alloreactivity.Immunobiology. 1979; 156: 2-12PubMed Google Scholar, Lechler and Lombardi, 1990Lechler R. Lombardi G. The structural basis of alloreactivity.Immunol. Res. 1990; 9: 135-146Crossref PubMed Scopus (17) Google Scholar), including the reasons for the high frequency of these T cells (Lindahl and Wilson, 1977Lindahl K.F. Wilson D.B. Histocompatibility antigen-activated cytotoxic T lymphocytes. I. Estimates of the absolute frequency of killer cells generated in vitro.J. Exp. Med. 1977; 145: 500-507Crossref PubMed Scopus (71) Google Scholar) and whether the peptide or the HLA molecule is more important in driving T cell alloreactivity (Bevan, 1984Bevan M.J. High determinant density may explain the phenomenon of alloreactivity.Immunol. Today. 1984; 5: 128-130Abstract Full Text PDF Scopus (165) Google Scholar, Matzinger and Bevan, 1977Matzinger P. Bevan M.J. Hypothesis: Why do so many lymphocytes respond to major histocompatibility antigens?.Cell. Immunol. 1977; 29: 1-5Crossref PubMed Scopus (372) Google Scholar). The HLA-centric model of alloreactivity considers that T cells concentrate on the polymorphic HLA residues irrespective of the bound peptide. For instance, the alloreactive murine 2C TCR adopts two very different binding orientations when bound to its host selecting-pMHC ligand versus an allogeneic pMHC target ligand, focusing instead on a mixture of allogeneic MHC differences and new peptide contacts (Colf et al., 2007Colf L.A. Bankovich A.J. Hanick N.A. Bowerman N.A. Jones L.L. Kranz D.M. Garcia K.C. How a single T cell receptor recognizes both self and foreign MHC.Cell. 2007; 129: 135-146Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar, Rossjohn and McCluskey, 2007Rossjohn J. McCluskey J. How a home-grown T cell receptor interacts with a foreign landscape.Cell. 2007; 129: 19-20Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). In contrast, the peptide-centric theory of allorecognition implies that the TCR exploits the similarities between the allogeneic and self-HLA molecule (“mimicry”) and recognizes the new set of endogenous peptides as foreign. Additionally, molecular mimicry is considered to underpin numerous T cell autoimmune disorders but has nevertheless been difficult to establish given the explicit requirement of the TCR to corecognize the antigens as well as the HLA molecules. Moreover, limited evidence so far suggests that T cell allorecognition is peptide centric (Archbold et al., 2008aArchbold J.K. Ely L.K. Kjer-Nielsen L. Burrows S.R. Rossjohn J. McCluskey J. Macdonald W.A. T cell allorecognition and MHC restriction—A case of Jekyll and Hyde?.Mol. Immunol. 2008; 45: 583-598Crossref PubMed Scopus (32) Google Scholar, Colf et al., 2007Colf L.A. Bankovich A.J. Hanick N.A. Bowerman N.A. Jones L.L. Kranz D.M. Garcia K.C. How a single T cell receptor recognizes both self and foreign MHC.Cell. 2007; 129: 135-146Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar, Reiser et al., 2000Reiser J.B. Darnault C. Guimezanes A. Grégoire 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 PubMed Scopus (183) Google Scholar, Speir et al., 1998Speir J.A. Garcia K.C. Brunmark A. Degano M. Peterson P.A. Teyton L. Wilson I.A. Structural basis of 2C TCR allorecognition of H-2Ld peptide complexes.Immunity. 1998; 8: 553-562Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar) and implicates polyspecificity as a mechanism leading to the high frequency of alloreactive T cells (Felix et al., 2007Felix N.J. Donermeyer D.L. Horvath S. Walters J.J. Gross M.L. Suri A. Allen P.M. Alloreactive T cells respond specifically to multiple distinct peptide-MHC complexes.Nat. Immunol. 2007; 8: 388-397Crossref PubMed Scopus (105) Google Scholar). However, it is still unclear whether dual recognition of disparate cognate and allogeneic pHLA by a single TCR can involve similar binding modes, namely operating via molecular mimicry (Archbold et al., 2008bArchbold J.K. Macdonald W.A. Burrows S.R. Rossjohn J. McCluskey J. T-cell allorecognition: A case of mistaken identity or déjà vu?.Trends Immunol. 2008; 29: 220-226Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, Rossjohn and McCluskey, 2007Rossjohn J. McCluskey J. How a home-grown T cell receptor interacts with a foreign landscape.Cell. 2007; 129: 19-20Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). Here we show that molecular mimicry can underpin human T cell alloreactivity. To investigate the molecular basis of natural human T cell alloreactivity, we examined the prototypic TCR termed LC13 that recognizes the immunodominant HLA-B∗0801-restricted epitope, FLRGRAYGL from EBNA 3A of Epstein-Barr virus (EBV) (Argaet et al., 1994Argaet V.P. Schmidt C.W. Burrows S.R. Silins S.L. Kurilla M.G. Doolan D.L. Suhrbier A. Moss D.J. Kieff E. Sculley T.B. Misko I.S. Dominant selection of an invariant T cell antigen receptor in response to persistent infection by Epstein-Barr virus.J. Exp. Med. 1994; 180: 2335-2340Crossref PubMed Scopus (244) Google Scholar, Burrows et al., 1994Burrows S.R. Khanna R. Burrows J.M. Moss D.J. An alloresponse in humans is dominated by cytotoxic T lymphocytes (CTL) cross-reactive with a single Epstein-Barr virus CTL epitope: implications for graft-versus-host disease.J. Exp. Med. 1994; 179: 1155-1161Crossref PubMed Scopus (246) Google Scholar). LC13 also alloreacts with HLA-B∗4402 and HLA-B∗4405, related allotypes that differ from each other by only one residue but differ from HLA-B∗0801 by 24 and 25 amino acids, respectively. Alloreactivity can be either dependent or independent of the HLA-bound peptide (Heath et al., 1989Heath W.R. Hurd M.E. Carbone F.R. Sherman L.A. Peptide-dependent recognition of H-2Kb by alloreactive cytotoxic T lymphocytes.Nature. 1989; 341: 749-752Crossref PubMed Scopus (150) Google Scholar, Heath et al., 1991Heath W.R. Kane K.P. Mescher M.F. Sherman L.A. Alloreactive T cells discriminate among a diverse set of endogenous peptides.Proc. Natl. Acad. Sci. USA. 1991; 88: 5101-5105Crossref PubMed Scopus (118) Google Scholar, Smith et al., 1997aSmith K.D. Huczko E. Engelhard V.H. Li Y.Y. Lutz C.T. Alloreactive cytotoxic T lymphocytes focus on specific major histocompatibility complex-bound peptides.Transplantation. 1997; 64: 351-359Crossref PubMed Scopus (15) Google Scholar, Smith et al., 1997bSmith P.A. Brunmark A. Jackson M.R. Potter T.A. Peptide-independent recognition by alloreactive cytotoxic T lymphocytes (CTL).J. Exp. Med. 1997; 185: 1023-1033Crossref PubMed Scopus (89) Google Scholar). Therefore, we examined whether LC13 allorecognition of HLA-B∗4405 required a specific peptide(s). Presentation of the HLA-B∗4405 alloantigen was examined in transfectants of the class-I-HLA-deficient mutant lymphoblastoid cell line (LCL) C1R and the TAP-deficient T2 cell line (Alexander et al., 1989Alexander J. Payne J.A. Murray R. Frelinger J.A. Cresswell P. Differential transport requirements of HLA and H-2 class I glycoproteins.Immunogenetics. 1989; 29: 380-388Crossref PubMed Scopus (131) Google Scholar). The C1R.B∗4405 cells, but not the parental C1R cells, were lysed by LC13 cytotoxic T-lymphocyte (CTL), indicating constitutive presentation of an allogeneic ligand by these cells (Figure 1A). However, coexpression of the viral TAP inhibitor ICP47 essentially abolished allorecognition of C1R-B∗4405 by LC13 (Figure 1A), indicating TAP dependence of this allogeneic ligand. Exogenous loading of C1R-B∗4405-ICP47 cells with viral peptide restored recognition by an antiviral CTL clone (DM1) (Archbold et al., 2009Archbold J.K. Macdonald W.A. Gras S. Ely L.K. Miles J.J. Bell M.J. Brennan R.M. Beddoe T. Wilce M.C.J. Clements C.S. et al.Natural micropolymorphism in human leukocyte antigens provides a basis for genetic control of antigen recognition.J. Exp. Med. 2009; 206: 209-219Crossref PubMed Scopus (76) Google Scholar) but did not restore killing by LC13 CTL (Figures 1A and 1B). The T2.B∗4405 cell line was not recognized by the human T cell line Jurkat coexpressing the LC13 αβ TCR and human CD8αβ genes (LC13.Jurkat) (Beddoe et al., 2009Beddoe T. Chen Z. Clements C.S. Ely L.K. Bushell S.R. Vivian J.P. Kjer-Nielsen L. Pang S.S. Dunstone M.A. Liu Y.C. et al.Antigen ligation triggers a conformational change within the constant domain of the alphabeta T cell receptor.Immunity. 2009; 30: 777-788Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). Stabilization of “empty” HLA-B∗4405 molecules with a HLA-B∗4405-binding peptide (DPα-peptide) did not sensitize the T2.B∗4405 cells for recognition by LC13.Jurkat (Figure 1C). Notably, the T2.B∗0801 and C1R.B∗0801 cell lines loaded with exogenous FLRGRAYGL viral peptide (“virotope”) activated LC13.Jurkat (Figures 1C and 1D), as did C1R.B∗4402 and C1R.B∗4405 transfectants (Figure 1D). Collectively, these data indicate that the alloreactivity of the LC13 TCR behaved in a peptide-dependent manner. A major hurdle in understanding the basis of alloreactivity is the identification of authentic antigenic peptides (the allopeptide[s]) bound to the allogeneic HLA molecule. Murine examples of alloreactive T cells have been the most informative to date, including the alloreactive BM3.3 TCR (Reiser et al., 2000Reiser J.B. Darnault C. Guimezanes A. Grégoire 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 PubMed Scopus (183) Google Scholar) and the 2C TCR (Colf et al., 2007Colf L.A. Bankovich A.J. Hanick N.A. Bowerman N.A. Jones L.L. Kranz D.M. Garcia K.C. How a single T cell receptor recognizes both self and foreign MHC.Cell. 2007; 129: 135-146Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar, Speir et al., 1998Speir J.A. Garcia K.C. Brunmark A. Degano M. Peterson P.A. Teyton L. Wilson I.A. Structural basis of 2C TCR allorecognition of H-2Ld peptide complexes.Immunity. 1998; 8: 553-562Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar) for which pMHC allopeptide structures are solved. However, pathogen-derived cognate ligands for the BM3.3 and 2C T cells remain unknown. To identify a candidate LC13 allopeptide(s), we generated insect cells expressing individual baculoviral constructs from a library of HLA-B∗4405 molecules covalently complexed with randomized peptides. Infected insect cells were screened for interaction with recombinant, bivalent LC13 TCR (Crawford et al., 2006Crawford F. Jordan K.R. Stadinski B. Wang Y. Huseby E. Marrack P. Slansky J.E. Kappler J.W. Use of baculovirus MHC/peptide display libraries to characterize T-cell receptor ligands.Immunol. Rev. 2006; 210: 156-170Crossref PubMed Scopus (54) Google Scholar). Repeated rounds of sorting allowed expansion of HLA-B∗4405-positive cells expressing a ligand that bound LC13 TCR (Figure 2A). Peptide insert sequences were obtained from 36 positive clones with 30 of these encoding the peptide EEYLKAWTF. Searching the human proteome for analogs of the EEYLKAWTF “mimotope” peptide identified two high-scoring matches (expect values of 283 and 65, respectively), each of 9 residues (EESLKDWYF and EEYLQAFTY) and therefore representing a potential natural “allotope.” These peptides shared 66% (6/9 identical residues) with the mimotope and possessed the P2E, P9Y/F anchor residues, features of B44-binding peptides. The peptide EESLKDWYF is derived from an ATPase but little is known about its physiologic role and expression. The peptide EEYLQAFTY is derived from an ATP binding cassette protein ABCD3 involved in transport of fatty acids into the peroxisome. We next examined recognition of the EESLKDWYF or EEYLQAFTY peptides by LC13.Jurkat cells (CD8+) and LC13 CTL. The EESLKDWYF peptide did not activate LC13.Jurkat cells and was not examined further because we conclude that this is not a bona fide alloligand for LC13 (not shown). In contrast, both the mimotope and EEYLQAFTY (hereafter allotope) peptides specifically sensitized exogenously loaded T2-B∗4405 cells (Figure 2B, middle) and C1R-B∗4405 cells expressing ICP47 (Figure 2B, right) for lysis by LC13 CTL. To determine whether the allotope is naturally presented, the impact of super transfection and knockdown of the ABCD3 gene was studied in cells naturally presenting B∗4405-restricted alloantigen to LC13. Super transfection of the ABCD3 gene into C1R.B∗4405 cells resulted in a modest increase in constitutive activation of LC13.Jurkat by C1R.B∗4405 and C1R.B∗4402 cells (Figure S1 available online). A specific RNAi construct was also used to knock down the natural, endogenous expression of ABCD3 in Ag-presenting cells (Figure 2C). Real-time PCR assays of RNA expression showed that the ABCD3 allotope RNAi reduced mRNA expression by >80% and confirmed the specificity of the RNAi constructs (semiquantitative RT-PCR inset, Figure 2C and Figure S2). Mock treatment of cells with irrelevant mβ-actin RNAi had no impact on LC13 allorecognition (Figure 2C, middle panel histograms). In contrast, introduction of the ABCD3 RNAi into the C1R.B∗4405 cells specifically reduced constitutive activation of LC13.Jurkat T cells by nearly 50% (p < 0.01) (Figure 2C, right panel histograms). Addition of exogenous allotope to the knocked down Ag-presenting cells restored full activation of the LC13.Jurkat T cells (Figure 2C). These data indicate that the ABCD3 allotope is an authentic, natural alloantigen recognized by the LC13 TCR. To understand the structural basis of the LC13 TCR alloreactivity, we determined the structures of the LC13 TCR in complex with the HLA-B∗4405 allotope and mimotope complexes to 2.6 Å and 2.7 Å resolution, respectively (Table 1, Tables S1 and S2). These structures were compared with the LC13-virotope complex (Kjer-Nielsen et al., 2003Kjer-Nielsen L. Clements C.S. Purcell A.W. Brooks A.G. Whisstock J.C. Burrows S.R. McCluskey J. Rossjohn J. A structural basis for the selection of dominant alphabeta T cell receptors in antiviral immunity.Immunity. 2003; 18: 53-64Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar).Table 1Data Collection and Refinement StatisticsData Collection StatisticsLC13-HLA B4405alloLC13-HLA B4405mimoTemperature100K100KSpace groupC2C2Cell dimensions (a,b,c) (Å, °)142.52, 54.24, 121.77; β = 114.43223.12, 53.22, 143.20; β = 102.39Resolution (Å)50-2.70 (2.80-2.70)aValues in parentheses are for highest-resolution shell.50-2.60 (2.69-2.60)Total number of observations70,144159,863Number of unique observations21,530 (1,278)50,197 (4,976)Multiplicity3.2 (2.0)3.2 (3.0)Data completeness (%)92.0 (55.6)97.8 (97.8)I/σI20.1 (2.4)12.5 (2.3)RmergebRmerge = Σ | Ihkl - < Ihkl > | / ΣIhkl. (%)5.9 (25.6)8.5 (41.1)Refinement StatisticsNonhydrogen atoms Protein6,65713,316 Water27124Resolution (Å)2.702.60RfactorcRfactor = Σhkl | | Fo | - | Fc | | / Σhkl | Fo | for all data except ≈5% that were used for Rfree calculation. (%)19.722.1RfreecRfactor = Σhkl | | Fo | - | Fc | | / Σhkl | Fo | for all data except ≈5% that were used for Rfree calculation. (%)26.927.8Rms deviations from ideality Bond lengths (Å)0.0090.006 Bond angles (°)1.2020.926Ramachandran plot (%) Most favored region87.190.5 Allowed region12.09.0Generously allowed region0.60.4a Values in parentheses are for highest-resolution shell.b Rmerge = Σ | Ihkl - < Ihkl > | / ΣIhkl.c Rfactor = Σhkl | | Fo | - | Fc | | / Σhkl | Fo | for all data except ≈5% that were used for Rfree calculation. Open table in a new tab The structure of the LC13 TCR-allotope complex was very similar to the mimotope complex with a root mean square deviation (rmsd) of 0.27 Å over the entire complex, and remarkably, both complexes (Figures 3A and 3B) were very similar to that of the LC13 TCR-virotope complex (Figure 3C; Kjer-Nielsen et al., 2003Kjer-Nielsen L. Clements C.S. Purcell A.W. Brooks A.G. Whisstock J.C. Burrows S.R. McCluskey J. Rossjohn J. A structural basis for the selection of dominant alphabeta T cell receptors in antiviral immunity.Immunity. 2003; 18: 53-64Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar) (rmsd between the allotope and mimotope complex versus the virotope complex was 0.87 Å and 0.77 Å, respectively). This similarity is reflected in the close superposition of the LC13 TCR in these complexes and their identical 60° docking modes across the long axis of the HLA (Figure 3D). Accordingly, the LC13 TCR location over the C terminus of the HLA-B∗4405 antigen-binding cleft mimicked the C-terminal docking of the LC13 TCR on the HLA-B∗0801-virotope complex (Kjer-Nielsen et al., 2002aKjer-Nielsen L. Clements C.S. Brooks A.G. Purcell A.W. Fontes M.R. McCluskey J. Rossjohn J. The structure of HLA-B8 complexed to an immunodominant viral determinant: peptide-induced conformational changes and a mode of MHC class I dimerization.J. Immunol. 2002; 169: 5153-5160PubMed Google Scholar, Kjer-Nielsen et al., 2003Kjer-Nielsen L. Clements C.S. Purcell A.W. Brooks A.G. Whisstock J.C. Burrows S.R. McCluskey J. Rossjohn J. A structural basis for the selection of dominant alphabeta T cell receptors in antiviral immunity.Immunity. 2003; 18: 53-64Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar). The total buried surface area (BSA) at the allotope, mimotope, and virotope complexes were all ≈2300 Å2 and moreover, the shape complementarity at the virotope, allotope, and mimotope interfaces with LC13 was very similar (0.59, 0.64, and 0.60, respectively). Both the Vα and Vβ domains of the LC13 TCR contributed roughly equally to the interfaces of the allotope, mimotope, and virotope complexes (range: Vα, 51.4%–56.2%, Vβ, 43.8%–48.6%), indicating that the LC13 alloreactivity is not driven by a skewed usage of the V domains at the TCR-pMHC interface unlike other alloreactive complexes (Colf et al., 2007Colf L.A. Bankovich A.J. Hanick N.A. Bowerman N.A. Jones L.L. Kranz D.M. Garcia K.C. How a single T cell receptor recognizes both self and foreign MHC.Cell. 2007; 129: 135-146Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar, Reiser et al., 2000Reiser J.B. Darnault C. Guimezanes A. Grégoire 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 PubMed Scopus (183) Google Scholar). Indeed, the number and nature of the LC13 TCR interactions with the pHLA B∗4405 in the allotope and mimotope complexes were also very similar to those of the LC13 TCR-virotope complex (allotope-mimotope-virotope: 146-160-135 van der Waals [v.d.w.] interactions, 15-13-14 H bonds, and 1 salt bridge each; Tabl" @default.
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• W2146652028 date "2009-12-01" @default.
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• W2146652028 title "T Cell Allorecognition via Molecular Mimicry" @default.
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• W2146652028 doi "https://doi.org/10.1016/j.immuni.2009.09.025" @default.
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