T-cell Receptor (TCR)-Peptide Specificity Overrides Affinity-enhancing TCR-Major Histocompatibility Complex Interactions

Cole, David K.; Miles, Kim; Madura, Florian; Holland, Christopher; Schauenburg, Andrea J. A.; Godkin, Andrew; Bulek, Anna; Fuller, Anna; Akpovwa, Hephzibah; Pymm, Phillip; Liddy, Nathaniel; Sami, Malkit; Li, Yang; Rizkallah, P.J.; Jakobsen, Bent K.; Sewell, Andrew K.

doi:10.1074/jbc.m113.522110

Cited by 60 publications

(62 citation statements)

References 63 publications

(101 reference statements)

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“…However, structural investigations of TCR-pMHC interactions have demonstrated that the TCR can establish a distinct and highly specific interaction with both peptide and MHC. In keeping with such specificity of binding requirements, even single mutations at key residues in the TCR, peptide, or MHC that are involved in the binding interface have been shown to abrogate antigen recognition (25–29). The importance of T-cell cross-reactivity is manifest not only in effective immune surveillance (2, 8) but also in autoreactivity (30) and the design of therapeutics (10, 11).…”

Section: Discussionmentioning

confidence: 99%

Structural Mechanism Underpinning Cross-reactivity of a CD8+ T-cell Clone That Recognizes a Peptide Derived from Human Telomerase Reverse Transcriptase

Cole

Berg

Lloyd

et al. 2017

Journal of Biological Chemistry

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T-cell cross-reactivity is essential for effective immune surveillance but has also been implicated as a pathway to autoimmunity. Previous studies have demonstrated that T-cell receptors (TCRs) that focus on a minimal motif within the peptide are able to facilitate a high level of T-cell cross-reactivity. However, the structural database shows that most TCRs exhibit less focused antigen binding involving contact with more peptide residues. To further explore the structural features that allow the clonally expressed TCR to functionally engage with multiple peptide-major histocompatibility complexes (pMHCs), we examined the ILA1 CD8+ T-cell clone that responds to a peptide sequence derived from human telomerase reverse transcriptase. The ILA1 TCR contacted its pMHC with a broad peptide binding footprint encompassing spatially distant peptide residues. Despite the lack of focused TCR-peptide binding, the ILA1 T-cell clone was still cross-reactive. Overall, the TCR-peptide contacts apparent in the structure correlated well with the level of degeneracy at different peptide positions. Thus, the ILA1 TCR was less tolerant of changes at peptide residues that were at, or adjacent to, key contact sites. This study provides new insights into the molecular mechanisms that control T-cell cross-reactivity with important implications for pathogen surveillance, autoimmunity, and transplant rejection.

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Section: Discussionmentioning

confidence: 99%

Structural Mechanism Underpinning Cross-reactivity of a CD8+ T-cell Clone That Recognizes a Peptide Derived from Human Telomerase Reverse Transcriptase

Cole

Berg

Lloyd

et al. 2017

Journal of Biological Chemistry

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“…4). Arg65 forms a charge-charge interaction with a Glu or Asp near the end of CDR2β in 4 of the 13 complexes, as well as a fifth crystallized with an engineered TCR (42). Three other TCRs use a Glu or Asp at the start of CDR1α to interact with Arg65.…”

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confidence: 99%

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

Blevins

Pierce

Singh

et al. 2016

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

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How T-cell receptors (TCRs) can be intrinsically biased toward MHC proteins while simultaneously display the structural adaptability required to engage diverse ligands remains a controversial puzzle. We addressed this by examining αβ TCR sequences and structures for evidence of physicochemical compatibility with MHC proteins. We found that human TCRs are enriched in the capacity to engage a polymorphic, positively charged "hot-spot" region that is almost exclusive to the α1-helix of the common human class I MHC protein, HLA-A*0201 (HLA-A2). TCR binding necessitates hot-spot burial, yielding high energetic penalties that must be offset via complementary electrostatic interactions. Enrichment of negative charges in TCR binding loops, particularly the germ-line loops encoded by the TCR Vα and Vβ genes, provides this capacity and is correlated with restricted positioning of TCRs over HLA-A2. Notably, this enrichment is absent from antibody genes. The data suggest a built-in TCR compatibility with HLA-A2 that biases receptors toward, but does not compel, particular binding modes. Our findings provide an instructional example for how structurally pliant MHC biases can be encoded within TCRs.T-cell receptor | peptide/MHC | structure | binding | MHC bias

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“…Although there are not yet enough published TCR‐pMHC structures to fully answer these questions, there are a number of examples that demonstrate that the system works under a high level of peptide specificity. Indeed, our own recent observations show that TCR‐peptide specificity is maintained even in the presence of affinity‐enhancing TCR‐MHC interactions . We further demonstrated that single amino acid substitutions in the MHC‐bound peptide, that had a minimal structural impact, could substantially reduce TCR binding indirectly by altering solvent interactions during binding .…”

Section: Introductionmentioning

confidence: 51%

The versatility of the αβ T‐cell antigen receptor

et al. 2014

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The T-cell antigen receptor is a heterodimeric ab protein (TCR) expressed on the surface of T-lymphocytes, with each chain of the TCR comprising three complementarity-determining regions (CDRs) that collectively form the antigen-binding site. Unlike antibodies, which are closely related proteins that recognize intact protein antigens, TCRs classically bind, via their CDR loops, to peptides (p) that are presented by molecules of the major histocompatibility complex (MHC). This TCR-pMHC interaction is crucially important in cell-mediated immunity, with the specificity in the cellular immune response being attributable to MHC polymorphism, an extensive TCR repertoire and a variable peptide cargo. The ensuing structural and biophysical studies within the TCRpMHC axis have been highly informative in understanding the fundamental events that underpin protective immunity and dysfunctional T-cell responses that occur during autoimmunity. In addition, TCRs can recognize the CD1 family, a family of MHC-related molecules that instead of presenting peptides are ideally suited to bind lipid-based antigens. Structural studies within the CD1-lipid antigen system are beginning to inform us how lipid antigens are specifically presented by CD1, and how such CD1-lipid antigen complexes are recognized by the TCR. Moreover, it has recently been shown that certain TCRs can bind to vitamin B based metabolites that are bound to an MHC-like molecule termed MR1. Thus, TCRs can recognize peptides, lipids, and small molecule metabolites, and here we review the basic principles underpinning this versatile and fascinating receptor recognition system that is vital to a host's survival.

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T-cell Receptor (TCR)-Peptide Specificity Overrides Affinity-enhancing TCR-Major Histocompatibility Complex Interactions

Cited by 60 publications

References 63 publications

Structural Mechanism Underpinning Cross-reactivity of a CD8+ T-cell Clone That Recognizes a Peptide Derived from Human Telomerase Reverse Transcriptase

Structural Mechanism Underpinning Cross-reactivity of a CD8+ T-cell Clone That Recognizes a Peptide Derived from Human Telomerase Reverse Transcriptase

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

The versatility of the αβ T‐cell antigen receptor

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