Complexes Closely Related Peptide:Class I Governs the Cross-Recognition of TCR CDR{{alpha}}3 Loop Docking Functional Evidence That Conserved (original) (raw)
The Journal of Immunology, 2001
The TCR recognizes its peptide:MHC (pMHC) ligand by assuming a diagonal orientation relative to the MHC helices, but it is unclear whether and to what degree individual TCRs exhibit docking variations when contacting similar pMHC complexes. We analyzed monospecific and cross-reactive recognition by diverse TCRs of an immunodominant HVH-1 glycoprotein B epitope (HSV-8p) bound to two closely related MHC class I molecules, H-2K b and H-2K bm8 . Previous studies indicated that the pMHC portion likely to vary in conformation between the two complexes resided at the N-terminal part of the complex, adjacent to peptide residues 2-4 and the neighboring MHC side chains. We found that CTL clones sharing TCR -chains exhibited disparate recognition patterns, whereas those with drastically different TCR-chains but sharing identical TCR␣ CDR3 loops displayed identical functional specificity. This suggested that the CDR␣3 loop determines the TCR specificity in our model, the conclusion supported by modeling of the TCR over the actual HSV-8:K b crystal structure. Importantly, these results indicate a remarkable conservation in CDR␣3 positioning, and, therefore, in docking of diverse TCR␣ heterodimers onto variant peptide:class I complexes, implying a high degree of determinism in thymic selection and T cell activation.
T Cell Receptor Binding Transition States and Recognition of Peptide/MHC
Biochemistry, 2007
T cell receptor recognition of peptide/MHC has been described as proceeding through a "twostep" process in which the TCR first contacts the MHC molecule prior to formation of the binding transition state using the germline-encoded CDR1 and CDR2 loops. The receptor then contacts the peptide using the hypervariable CDR3 loops as the transition state decays to the bound state. The model subdivides TCR binding into peptide-independent and peptide-dependent steps, demarcated at the binding transition state. Investigating the two-step model, here we show that two TCRs that recognize the same peptide/ MHC bury very similar amounts of solvent-accessible surface area in their transition states. However, 1300-1500 Å 2 of surface area is buried in each, a significant amount suggestive of participation of peptide and associated CDR3 surface. Consistent with this interpretation, analysis of peptide and TCR variants indicates that stabilizing contacts to the peptide are formed within both transition states. These data are incompatible with the original two-step model, as are transition state models built using the principle of minimal frustration commonly employed in the investigation of protein folding and binding transition states. These findings will be useful in further explorations of the nature of TCR binding transition states, as well as ongoing efforts to understand the mechanisms by which T cell receptors recognize the composite peptide/MHC surface.
TcR Recognition of the MHC-Peptide Dimer: Structural Properties of a Ternary Complex
Journal of Molecular Biology, 1996
We have developed a method that utilizes site-specific mutation data, sequence analysis, immunological data and free-energy minimization, to Iowa State University determine structural features of the ternary complex formed by the T-cell Ames, IA 50011, USA receptor (TcR) and the class I major histocompatibility complex (MHC) 2 Department of Biomedical molecule bound by peptide. The analysis focuses on the mouse K d MHC Engineering, Boston system, for which a large set of clones with sequenced T-cell receptors is University, College of available for specific peptides.
Journal of Experimental Medicine, 2004
Major histocompatibility complex (MHC) class I variants H-2K b and H-2K bm8 differ primarily in the B pocket of the peptide-binding groove, which serves to sequester the P2 secondary anchor residue. This polymorphism determines resistance to lethal herpes simplex virus (HSV-1) infection by modulating T cell responses to the immunodominant glycoprotein B 498-505 epitope, HSV8. We studied the molecular basis of these effects and confirmed that T cell receptors raised against K b -HSV8 cannot recognize H-2K bm8 -HSV8. However, substitution of Ser P2 to Glu P2 (peptide H2E) reversed T cell receptor (TCR) recognition; H-2K bm8 -H2E was recognized whereas H-2K b -H2E was not. Insight into the structural basis of this discrimination was obtained by determining the crystal structures of all four MHC class I molecules in complex with bound peptide (pMHCs). Surprisingly, we find no concerted pMHC surface differences that can explain the differential TCR recognition. However, a correlation is apparent between the recognition data and the underlying peptide-binding groove chemistry of the B pocket, revealing that secondary anchor residues can profoundly affect TCR engagement through mechanisms distinct from the alteration of the resting state conformation of the pMHC surface.
How the T Cell Receptor Sees Antigen—A Structural View
Cell, 2005
sive reviews to which we direct the reader (Hennecke and Wiley, 2001; Housset and Malissen, 2003; Rudolph Departments of Microbiology & Immunology et al., 2002). and Structural Biology The Inherent Reactivity of the TCR for Peptide-MHC Howard Hughes Medical Institute The interface between an αβ TCR and pMHC repre-Stanford University School of Medicine sents the structural solution to almost 400 million years Stanford, California 94305 of coevolution. While we can describe this solution in great structural detail gleaned from structures of approximately twelve unique TCR/pMHC complexes Structures of many of the cell surface receptor-ligand (Housset and Malissen, 2003; Rudolph et al., 2002), the complexes mediating the interactions between T cells
MOLECULAR INTERACTIONS MEDIATING T CELL ANTIGEN RECOGNITION
Annual Review of Immunology, 2003
Over the past decade, key protein interactions contributing to T cell antigen recognition have been characterized in molecular detail. These have included interactions involving the T cell antigen receptor (TCR) itself, its coreceptors CD4 and CD8, the accessory molecule CD2, and the costimulatory receptors CD28 and CTLA-4. A clear view is emerging of how these molecules interact with their ligands at the cellcell interface. Structural and binding studies have confirmed that the proteins span small but comparable distances and that, overall, they interact very weakly. However, there have been important surprises as well: that TCR interactions with peptide-MHC are topologically constrained and characterized by considerable conformational flexibility at the binding interface; that coreceptors engage peptide-MHC with extraordinarily fast kinetics and at angles apparently precluding direct interactions with the TCR bound to the same peptide-MHC; that the structural mechanisms allowing recognition by costimulatory and accessory molecules to be weak and yet specific are very heterogeneous; and that because of differences in both binding affinity and stoichiometry, there is enormous variation in the stability of the various costimulatory receptor/ligand complexes. These studies provide the necessary framework for exploring how these molecular interactions initiate T cell activation. 0732-0582/03/0407-0659$14.00 659 Annu. Rev. Immunol. 2003.21:659-684. Downloaded from arjournals.annualreviews.org by University of Oxford -Nuffield College on 07/02/09. For personal use only.
Immunity, 2005
the helical surface )%57-%07ف( is conserved and evolved for biased recognition by the TCR, suggests that TCR/pMHC interactions are tuned for the sampling of different antigens (Daniel et al.). and Structural Biology In support of this hypothesis, examples exist of struc-Stanford University School of Medicine turally diverse, crossreactive peptides to a single T cell Stanford, California 94305 clone (Bhardwaj et al., 1993; Crawford et al., 2004; Hag-2 Torrey Pines Institute for Molecular Studies erty and Allen, 1995; Hemmer et al., 1998a; Ignatowicz San Diego, California 92121 et al., 1997; Kersh and Allen, 1996b; Krogsgaard et al., 2003; Loftus et al., 1999; Reiser et al., 2003; Sykulev et al., 1994; Wucherpfennig and Strominger, 1995). While some of these peptides retain recognizable sequence Summary similarities with the cognate peptides (Crawford et al., 2004; Krogsgaard et al., 2003; Sykulev et al., 1998), other T cell receptor crossreactivity with different peptide crossreactive peptides have been shown to be minimally ligands and biased recognition of MHC are coupled homologous in sequence and therefore presumably enfeatures of antigen recognition that are necessary for gaging the TCR though a unique structural solution the T cell's diverse functional repertoire. In the crystal (Lang et al., 2002; Loftus et al., 1999; Reiser et al., 2003; structure between an autoreactive, EAE T cell clone Wucherpfennig, 2004). 172.10 and myelin basic protein (1-11) presented by In contradiction to the notion of a promiscuous TCR, class II MHC I-A u , recognition of the MHC is dominated most T cell clones are exquisitely sensitive to mutations by the V domain of the TCR, which interacts with the in the peptide (Shih and Allen, 2004). Some of the most MHC ␣ chain in a manner suggestive of a germlineextensively studied TCR/MHC systems, such as 2B4/ encoded TCR/MHC "anchor point." Strikingly, there I-E k (Krogsgaard et al., 2003), 3L.2/I-E k (Kersh et al., are few specific contacts between the TCR CDR3 1998; Shih and Allen, 2004), KRN/I-A g7 (Basu et al., 2000), loops and the MBP peptide. We also find that over and 2C/H-2K b (Degano et al., 2000; Sykulev et al., 1996), 1,000,000 different peptides derived from combinatoexhibit extremely specific peptide recognition and are rial libraries can activate 172.10, yet the TCR strongly largely intolerant of amino acid changes in the TCR conprefers the native MBP contact residues. We suggest tacts. In most reported cases of degenerate TCR recogthat while TCR scanning of pMHC may be degenerate nition, the TCR contact residues of the crossreactive due to the TCR germline bias for MHC, recognition of peptides are similar (Basu et al., 2000; Crawford et al., structurally distinct agonist peptides is not indicative 2004; Grogan et al., 1999; Sykulev et al., 1998; Wilson of TCR promiscuity, but rather highly specific alternaet al., 1999). Indeed, a single centrally located peptide tive solutions to TCR engagement. residue is sufficient to produce tight selectivity by a TCR (Degano et al., 2000; Ding et al., 1998; Krogsgaard et al., Introduction 2003; Shih and Allen, 2004). Thus, the idea of degenerate T cell recognition is difficult to reconcile with experimen-The engagement of the T cell receptor by peptide-MHC tal observations of T cell specificity. is the central antigen-specific event mediating the cellu-To address these questions, we have been studying lar immune response. The concept of an inherent TCR TCR/pMHC interactions in murine experimental allergic degeneracy has emerged to explain how a TCR is able encephalomyelitis (EAE), an intensively studied model to recognize the diverse peptide antigens it encounters system, to understand autoimmunity to neural self-antiduring the processes of thymic education and peripheral gens, such as myelin basic protein (MBP) (Zamvil and surveillance (Ignatowicz et al., 1997; Nikolic-Zugic and Steinman, 1990). The immunodominant encephalito-Bevan, 1990; Hemmer et al., 1998b; Holler and Kranz, genic T cell epitope of MBP, recognized by T cells in 2004; Kersh and Allen, 1996a; Mason, 1998; Wuchermice of the H-2 u haplotype (PL/J or B10.PL), is the acetpfennig, 2004). This concept has been buttressed by ylated N-terminal 11-mer (Ac1-11) (Zamvil et al., 1987). biophysical studies of TCR/MHC interactions (Rudolph The Ac1-11 epitope in the context of class II MHC I-A u and Wilson, 2002), which indicate that flexibility in the has a number of unusual features such as a very short central CDR3 loops of the TCR may serve as an adaptahalf-life (Ͻ15 min.) and a requirement for an N-terminal tion mechanism to "read out" different peptide antigens acetylation, and MBP peptides as short as Ac1-6 can during TCR "scanning" of the universe of peptide-MHC still activate EAE T cell clones (Fairchild et al.Mason et al., The fact that peptide comprises a fraction )%03-%52ف( 1995; Wraith et al., 1992). A crystal structure of I-A u of the composite pMHC surface, while the majority of complexed with MBP1-11 provided a rationale for these properties by finding that the peptide sits in an unusual shifted register in the groove, which results in empty p1 *Correspondence: kcgarcia@stanford.edu 3 These authors contributed equally to this work. and p2 pockets, the MBP N terminus in the p3 pocket, Immunity 82 model included A2-A116 (the ␣ chain of TCR), B3-B117 (the  chain of TCR), C1-C181 (the ␣ chain of I-A u ), D1-D190 (the  chain of I-A u ), Received: August 11, 2004 and P-3-P8 (p-3-P0 is part of the linker and P1-P8 is the MBP Revised: October 7, 2004 peptide). Repeated iterations between manual rebuilding and mini-Accepted: November 17, 2004 mization as well as B factor refinement resulted in a model with R Published: January 25, 2005 factors of 24.3% and R free of 27.4%. The stereochemistry of the structure was analyzed with PROCHECK (Laskowski et al., 1993). References Details of the refinement statistics are given in Supplemental Table S1. Libraries and Peptides Steinman, L. (1988). Limited heterogeneity of T cell receptors from Libraries and biased sublibrary mixtures were prepared at Mixture lymphocytes mediating autoimmune encephalomyelitis allows spe-Sciences, Inc. (San Diego, CA) as described previously (Pinilla et cific immune intervention. Cell 54, 263-273. al., 1994). PCL 97-4 is a synthetic N-acetylated, C-terminal amide, L-amino acid combinatorial decapeptide library arrayed in a posi-Anderton, S.M., Manickasingham, S.P., Burkhart, C., Luckcuck, T.A., Holland, S.J., Lamont, A.G., and Wraith, D.C. (1998). Fine specificity tional scanning format. It consists of 200 mixtures in the OX 9 format, Structure of an Autoimmune TCR/Peptide-MHC Complex 91 of the myelin-reactive T cell repertoire: implications for TCR antago-peptide can induce clinical signs of experimental autoimmune encephalomyelitis. J. 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TCR Recognition of Peptide–MHC-I: Rule Makers and Breakers
International Journal of Molecular Sciences, 2020
T cells are a critical part of the adaptive immune system that are able to distinguish between healthy and unhealthy cells. Upon recognition of protein fragments (peptides), activated T cells will contribute to the immune response and help clear infection. The major histocompatibility complex (MHC) molecules, or human leukocyte antigens (HLA) in humans, bind these peptides to present them to T cells that recognise them with their surface T cell receptors (TCR). This recognition event is the first step that leads to T cell activation, and in turn can dictate disease outcomes. The visualisation of TCR interaction with pMHC using structural biology has been crucial in understanding this key event, unravelling the parameters that drive this interaction and their impact on the immune response. The last five years has been the most productive within the field, wherein half of current unique TCR–pMHC-I structures to date were determined within this time. Here, we review the new insights le...