How a Single T Cell Receptor Recognizes Both Self and Foreign MHC

Howard Hughes Medical Institute, Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell (Impact Factor: 32.24). 05/2007; 129(1):135-46. DOI: 10.1016/j.cell.2007.01.048
Source: PubMed


alphabeta T cell receptors (TCRs) can crossreact with both self- and foreign- major histocompatibility complex (MHC) proteins in an enigmatic phenomenon termed alloreactivity. Here we present the 2.35 A structure of the 2C TCR complexed with its foreign ligand H-2L(d)-QL9. Surprisingly, we find that this TCR utilizes a different strategy to engage the foreign pMHC in comparison to the manner in which it recognizes a self ligand H-2K(b)-dEV8. 2C engages both shared and polymorphic residues on L(d) and K(b), as well as the unrelated QL9 and dEV8 peptide antigens, in unique pair-wise contacts, resulting in greater structural complementarity with the L(d)-QL9 complex. In the structure of an engineered, high-affinity 2C TCR variant bound to H-2L(d)-QL9, the "wild-type" TCR-MHC binding orientation persists despite modified TCR-CDR3alpha interactions with peptide. Thus, a single TCR recognizes two globally similar, but distinct ligands by divergent mechanisms, indicating that receptor-ligand crossreactivity can occur in the absence of molecular mimicry.

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Available from: Alexander John Bankovich, Feb 19, 2015
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    • "Although we believe this mechanism will be general for ab TCRs, recognition of nonhomologous antigens certainly occurs to varying degrees in the TCR repertoire, although molecularly defined examples are surprisingly rare. The ability for one TCR to bind to multiple MHCs (e.g., alloreactivity), for one TCR to bind in multiple orientations on one MHC, for a peptide to noncanonically bind MHC (e.g., partially filled MHC grooves, registershifted peptides), or for a TCR to have TCR-peptide contacts as a disproportionately large or small part of the overall interface (e.g., ''super-bulged'' peptides) will grant some receptors a greater degree of epitope promiscuity (Adams et al., 2011; Colf et al., 2007; Maynard et al., 2005; Morris and Allen, 2012; Morris et al., 2011; Tynan et al., 2005). It is also possible that class I versus class II MHC-specific TCRs could exhibit different degrees of cross-reactivity as a consequence of the ''low-lying'' peptides in the class II groove, versus the elevated or ''higherprofile'' peptides presented by class I. Indeed, in a prior study, multiple peptides reactive with a class I-specific (H-2L d ) murine TCR were identified through manual curation, and the structures indicated a diverse recognition chemistry by the TCR CDR3 loops (Adams et al., 2011). "
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    ABSTRACT: In order to survey a universe of major histocompatibility complex (MHC)-presented peptide antigens whose numbers greatly exceed the diversity of the T cell repertoire, T cell receptors (TCRs) are thought to be cross-reactive. However, the nature and extent of TCR cross-reactivity has not been conclusively measured experimentally. We developed a system to identify MHC-presented peptide ligands by combining TCR selection of highly diverse yeast-displayed peptide-MHC libraries with deep sequencing. Although we identified hundreds of peptides reactive with each of five different mouse and human TCRs, the selected peptides possessed TCR recognition motifs that bore a close resemblance to their known antigens. This structural conservation of the TCR interaction surface allowed us to exploit deep-sequencing information to computationally identify activating microbial and self-ligands for human autoimmune TCRs. The mechanistic basis of TCR cross-reactivity described here enables effective surveillance of diverse self and foreign antigens without necessitating degenerate recognition of nonhomologous peptides.
    Cell 05/2014; 157(5):1073-87. DOI:10.1016/j.cell.2014.03.047 · 32.24 Impact Factor
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    • "Therefore, molecular mimicry likely attributes to the observed cross-reactivity between these epitopes. On the other hand, cross-reactive TCR in mice can dock to self-MHC:peptide complexes in a different orientation than to allogeneic MHC:peptide complexes, suggesting that cross-reactivity can be established without molecular mimicry [80]. Thus, direct alloreactivity is a complex immune response that can only partially be explained by molecular mimicry. "
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    ABSTRACT: Human leukocyte Antigen (HLA) mismatching leads to severe complications after solid-organ transplantation and hematopoietic stem-cell transplantation. The alloreactive responses underlying the posttransplantation complications include both direct recognition of allogeneic HLA by HLA-specific alloantibodies and T cells and indirect T-cell recognition. However, the immunogenicity of HLA mismatches is highly variable; some HLA mismatches lead to severe clinical B-cell- and T-cell-mediated alloreactivity, whereas others are well tolerated. Definition of the permissibility of HLA mismatches prior to transplantation allows selection of donor-recipient combinations that will have a reduced chance to develop deleterious host-versus-graft responses after solid-organ transplantation and graft-versus-host responses after hematopoietic stem-cell transplantation. Therefore, several methods have been developed to predict permissible HLA-mismatch combinations. In this review we aim to give a comprehensive overview about the current knowledge regarding HLA-directed alloreactivity and several developed in vitro and in silico tools that aim to predict direct and indirect alloreactivity.
    Research Journal of Immunology 04/2014; 2014(11):159479. DOI:10.1155/2014/159479
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    • "For the few positively selecting self peptides that have been described for particular monoclonal TCRs, there is no evidence that sequence resemblance to agonist peptides beyond key residues anchoring the peptide to the MHC binding groove is a necessary feature of selecting peptides (Berg et al., 1999; Ebert et al., 2009; Lo et al., 2009; Santori et al., 2002; Sasada et al., 2001). It may be that the positioning of the epitopic residues recognized by the TCR CDR3 regions with respect to these anchor sites plays an important role in the self-foreign binding relationship we report here (Garcia et al., 2009; Germain , 1990) or the ability of TCRs to specifically interact with structurally different ligands in the same general orientation but with slightly different strategies (Colf et al., 2007; Felix et al., 2007) account for these observations. In either case, our findings argue for revisiting the issue of how pMHC recognition occurs and what structural elements of the TCR and pMHC might support the unanticipated ability of T cells selected on self to bind well to foreign peptides bound to the same MHC molecule. "
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    ABSTRACT: Developing T cells express diverse antigen receptors whose specificities are not prematched to the foreign antigens they eventually encounter. Past experiments have revealed that thymocytes must productively signal in response to self antigens to mature and enter the peripheral T cell pool (positive selection), but how this process enhances effective mature T cell responses to foreign antigen is not fully understood. Here we have documented an unsuspected connection between thymic recognition events and foreign antigen-driven T cell responses. We find that the strength of self-reactivity is a clone-specific property unexpectedly directly related to the strength of T cell receptor (TCR) binding to presented foreign antigen. T cells with receptors showing stronger interaction with self dominate in responses to infections and accumulate in aging individuals, revealing that positive selection contributes to effective immunity by skewing the mature TCR repertoire toward highly effective recognition of pathogens that pose a danger to the host.
    Immunity 12/2012; 38(2). DOI:10.1016/j.immuni.2012.09.011 · 21.56 Impact Factor
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