How structural adaptability exists alongside HLA-A2 bias in the human αβ TCR repertoire

Blevins, Sydney J.; Pierce, Brian G.; Singh, Nishant K.; Riley, Timothy P.; Wang, Yuan; Spear, Timothy T.; Nishimura, Michael I.; Weng, Zhiping; Baker, Brian M.

doi:10.1073/pnas.1522069113

Cited by 53 publications

(71 citation statements)

References 85 publications

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“…There are multiple electrostatic interactions between the TCR and the length of the α2-helix. These interactions include a saltbridge from Asp30 of CDR1β to Lys146, which is also observed in other complexes with A2 (30). Another salt-bridge is formed between Lys60 of CDR2α and Glu154, and hydrogen bonds are made to Ala149 and Thr163 from residues in CDR3β and CDR1α, respectively.…”

Section: Resultssupporting

confidence: 55%

“…Tyr50 of CDR2β is aligned alongside the helix as commonly observed in many TCR-pMHC complexes (31), contacting Ala69 and Gln72. Glu56β forms a salt-bridge with Arg75, an interaction less frequently observed in TCR complexes but present in several structures of TCRs with A2 (30).…”

Section: Resultsmentioning

confidence: 97%

“…4 A and C). The Arg65/Lys66 combination is essentially exclusive to A2, and the engagement of this region via electrostatic interactions from CDR1α and CDR3α is a distinctive feature of TCRs that bind A2, influencing the position of the TCR as well as the composition of TCR loops (30).…”

Section: Resultsmentioning

confidence: 99%

“…Further down the α1-helix, Arg65 and Lys66 form the cluster of positive charge that is almost exclusive to A2 and helps orient A2-binding TCRs on the MHC (30). Arg65 is glutamine in the B proteins and in >99% of the C proteins, and Lys66 is asparagine in the other A proteins and isoleucine in the B proteins.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, the HCV1406-NS3/A2 complex displays the hallmarks of TCRs that bind A2, most notably the accommodation of the positive charges on Arg65 and Lys66. We recently presented evidence that, given the high frequency of A2 in human populations, the need to offset this charge cluster has influenced the composition of TCR genes, leading to biased recognition and restricted TCR positioning (30). Therefore, although geometrical requirements for coreceptor and CD3 compatibility could influence HCV1406 binding, the complex displays features associated with TCR-MHC coevolution and a subsequent inherent bias of TCRs for MHC proteins.…”

Section: Discussionmentioning

confidence: 99%

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How an alloreactive T-cell receptor achieves peptide and MHC specificity

Wang

Singh

Spear

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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T-cell receptor (TCR) allorecognition is often presumed to be relatively nonspecific, attributable to either a TCR focus on exposed major histocompatibility complex (MHC) polymorphisms or the degenerate recognition of allopeptides. However, paradoxically, alloreactivity can proceed with high peptide and MHC specificity. Although the underlying mechanisms remain unclear, the existence of highly specific alloreactive TCRs has led to their use as immunotherapeutics that can circumvent central tolerance and limit graft-versus-host disease. Here, we show how an alloreactive TCR achieves peptide and MHC specificity. The HCV1406 TCR was cloned from T cells that expanded when a hepatitis C virus (HCV)-infected HLA-A2 − individual received an HLA-A2 + liver allograft. HCV1406 was subsequently shown to recognize the HCV nonstructural protein 3 (NS3):1406-1415 epitope with high specificity when presented by HLA-A2. We show that NS3/HLA-A2 recognition by the HCV1406 TCR is critically dependent on features unique to both the allo-MHC and the NS3 epitope. We also find cooperativity between structural mimicry and a crucial peptide "hot spot" and demonstrate its role, along with the MHC, in directing the specificity of allorecognition. Our results help explain the paradox of specificity in alloreactive TCRs and have implications for their use in immunotherapy and related efforts to manipulate TCR recognition, as well as alloreactivity in general.T-cell receptor | peptide-MHC | structure | alloreactivity | specificity

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Section: Resultssupporting

confidence: 55%

Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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How an alloreactive T-cell receptor achieves peptide and MHC specificity

Wang

Singh

Spear

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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ATLAS: A database linking binding affinities with structures for wild-type and mutant TCR-pMHC complexes

et al. 2017

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The ATLAS (Altered TCR Ligand Affinities and Structures) database (https://zlab.umassmed.edu/atlas/web/) is a manually curated repository containing the binding affinities for wild-type and mutant T cell receptors (TCRs) and their antigens, peptides presented by the major histocompatibility complex (pMHC). The database links experimentally measured binding affinities with the corresponding three dimensional (3D) structures for TCR-pMHC complexes. The user can browse and search affinities, structures, and experimental details for TCRs, peptides, and MHCs of interest. We expect this database to facilitate the development of next-generation protein design algorithms targeting TCR-pMHC interactions. ATLAS can be easily parsed using modeling software that builds protein structures for training and testing. As an example, we provide structural models for all mutant TCRs in ATLAS, built using the Rosetta program. Utilizing these structures, we report a correlation of 0.63 between experimentally measured changes in binding energies and our predicted changes.

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Geometrical characterization of T cell receptor binding modes reveals class‐specific binding to maximize access to antigen

et al. 2019

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Recognition of antigenic peptides bound to major histocompatibility complex (MHC) proteins by αβ T cell receptors (TCRs) is a hallmark of T cell mediated immunity. Recent data suggest that variations in TCR binding geometry may influence T cell signaling, which could help explain outliers in relationships between physical parameters such as TCR‐pMHC binding affinity and T cell function. Traditionally, TCR binding geometry has been described with simple descriptors such as the crossing angle, which quantifies what has become known as the TCR's diagonal binding mode. However, these descriptors often fail to reveal distinctions in binding geometry that are apparent through visual inspection. To provide a better framework for relating TCR structure to T cell function, we developed a comprehensive system for quantifying the geometries of how TCRs bind peptide/MHC complexes. We show that our system can discern differences not clearly revealed by more common methods. As an example of its potential to impact biology, we used it to reveal differences in how TCRs bind class I and class II peptide/MHC complexes, which we show allow the TCR to maximize access to and “read out” the peptide antigen. We anticipate our system will be of use in not only exploring these and other details of TCR‐peptide/MHC binding interactions, but also addressing questions about how TCR binding geometry relates to T cell function, as well as modeling structural properties of class I and class II TCR‐peptide/MHC complexes from sequence information. The system is available at https://tcr3d.ibbr.umd.edu/tcr_com or for download as a script.

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How structural adaptability exists alongside HLA-A2 bias in the human αβ TCR repertoire

Cited by 53 publications

References 85 publications

How an alloreactive T-cell receptor achieves peptide and MHC specificity

How an alloreactive T-cell receptor achieves peptide and MHC specificity

ATLAS: A database linking binding affinities with structures for wild-type and mutant TCR-pMHC complexes

Geometrical characterization of T cell receptor binding modes reveals class‐specific binding to maximize access to antigen

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