T-cell Receptor Specificity Maintained by Altered Thermodynamics

Madura, Florian; Rizkallah, P.J.; Miles, Kim; Holland, Christopher; Bulek, Anna; Fuller, Anna; Schauenburg, Andrea J. A.; Miles, John J.; Liddy, Nathaniel; Sami, Malkit; Li, Yi; Hossain, Moushumi; Baker, Brian M.; Jakobsen, Bent K.; Sewell, Andrew K.; Cole, David K.

doi:10.1074/jbc.m113.464560

Cited by 39 publications

(70 citation statements)

References 53 publications

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“…One difference is the larger number of interfacial hydrogen bonding interactions for JM22, seven, as compared to one or two for the other TCRs. While buried hydrogen bonds are not expected to contribute significantly to the overall binding energy, differential organization of bound solvent in the TCR-peptide-MHC interface has been implicated as playing a role in affinity determination for these complexes 44 , and interfacial hydrogen bonding might influence this. We did not obtain detailed structural information for non-bound LS10 or LS01 TCR, but binding-induced conformational changes have been suggested to play a role in affinity determination through entropic effects for JM22 14 .…”

Section: Discussionmentioning

confidence: 99%

Broad TCR repertoire and diverse structural solutions for recognition of an immunodominant CD8+ T cell epitope

Song

Gil

Mishra

et al. 2017

Nat Struct Mol Biol

121

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A keystone of antiviral immunity is CD8 T-cell recognition of viral peptides bound to MHC-I proteins. The recognition mode of individual T cell receptors (TCRs) has been studied in some detail, but how TCR variation functions in providing a robust response to viral antigen is unclear. The influenza M1 epitope is an immunodominant target of CD8 T cells helping to control influenza in HLA-A2+ individuals. Here, we show that many distinct TCRs are used by CD8 T cells to recognize HLA-A2/M1, encoding different structural solutions to the problem of specifically recognizing a relatively featureless peptide antigen. The vast majority of responding TCRs target small clefts between peptide and MHC. These broad repertoires lead to plasticity in antigen recognition and protection against T cell clonal loss and viral escape.

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Section: Discussionmentioning

confidence: 99%

Broad TCR repertoire and diverse structural solutions for recognition of an immunodominant CD8+ T cell epitope

Song

Gil

Mishra

et al. 2017

Nat Struct Mol Biol

121

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“…4. It is well known that the mutations in CDR1/2 regions upregulate the overall TCR:pMHC affinity by mainly enhancing the affinity between TCR and MHC but not TCR and pMHC (68, 69). Accordingly, high affinity TCRs with CDR1/2 mutations often lead to the loss of peptide specificity (56, 70).…”

Section: Discussionmentioning

confidence: 99%

Specific Roles of Each TCR Hemichain in Generating Functional Chain-Centric TCR

Nakatsugawa

Yamashita

Ochi

et al. 2015

The Journal of Immunology

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T cell receptor (TCR)α and β chains cooperatively recognize peptide-MHC (pMHC) complexes. It has been shown that a ‘chain-centric’ TCR hemichain can, by itself, dictate MHC-restricted antigen specificity without requiring major contributions from the paired TCR counterchain. Little is known, however, regarding the relative contributions and roles of chain-centric and its counter, non-chain-centric hemichains in determining T cell avidity. We comprehensively analyzed a thymically unselected T cell repertoire generated by transducing the α chain-centric HLA-A*02:01(A2)/MART127–35 TCRα, clone SIG35α, into A2-matched and unmatched post-thymic T cells. Regardless of their HLA-A2 positivity, a substantial subset of peripheral T cells transduced with SIG35α gained reactivity for A2/MART127–35. While the generated A2/MART127–35-specific T cells used various TRBV genes, TRBV27 predominated with >102 highly diverse and unique clonotypic CDR3β sequences. T cells individually reconstituted with various A2/MART127–35 TRBV27 TCRβ genes along with SIG35α possessed a wide range (>2 log orders) of avidity. Approximately half possessed avidity higher than T cells expressing clone DMF5, a naturally occurring A2/MART127–35 TCR with one of the highest affinities. Importantly, similar findings were recapitulated with other self-antigens. Our results indicate that, although a chain-centric TCR hemichain determines antigen specificity, the paired counterchain can regulate avidity over a broad range (>2 log orders) without compromising antigen specificity. TCR chain centricity can be exploited to generate a thymically unselected antigen-specific T cell repertoire, which can be used to isolate high avidity antitumor T cells and their uniquely encoded TCRs rarely found in the periphery due to tolerance.

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“…Some of these examples are summarized in a recent analysis of several structures (32). In some cases, germline-encoded CDR1 loops interface with the N-terminal or C-terminal halves of peptides, contributing to peptide specificity (33–35). Conformations of neighboring CDR loops can influence one another (36–38).…”

Section: Rules Are Made To Be Broken and Roles Are Not Easily Definedmentioning

confidence: 99%

“…Returning to the example of A6 TCR, the germline CDR1β loop forms a very strong hydrogen bond with the C-terminal end of the Tax 11-19 peptide, resulting in high specificity for a tyrosine at P8 (29, 30). In another case, the Mel5 TCR forms a specificity-determining salt-bridge with Glu1 of the MART-1 26-35 peptide using the germline CDR1α loop (33, 34). The HCV1406 TCR which recognizes the HCV NS3 epitope requires a lysine at P1, which is also engaged by CDR1α (35).…”

Section: Rationalizing the Specificity/cross-reactivity Duality Of Tcrsmentioning

confidence: 99%

Emerging Concepts in TCR Specificity: Rationalizing and (Maybe) Predicting Outcomes

Singh

Riley

Baker

et al. 2017

The Journal of Immunology

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T cell specificity emerges from a myriad of processes, ranging from the biological pathways that control T cell signaling to the structural and physical mechanisms that influence how TCRs bind antigen/MHC. Of these processes, the binding specificity of the TCR is a key component. However, TCR specificity is enigmatic: TCRs are at once specific but also cross-reactive. Although long-appreciated, this duality continues to puzzle immunologists and has implications for the development of TCR-based therapeutics. Here we review TCR specificity, emphasizing results that have emerged from structural and physical studies of TCR binding. We show how the TCR specificity/cross-reactivity duality can be rationalized from structural and biophysical principles. There is excellent agreement between predictions from these principles and classic predictions about the scope of TCR cross-reactivity. We demonstrate how these same principles can also explain amino acid preferences in immunogenic epitopes and highlight opportunities for structural considerations in predictive immunology.

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T-cell Receptor Specificity Maintained by Altered Thermodynamics

Cited by 39 publications

References 53 publications

Broad TCR repertoire and diverse structural solutions for recognition of an immunodominant CD8+ T cell epitope

Broad TCR repertoire and diverse structural solutions for recognition of an immunodominant CD8+ T cell epitope

Specific Roles of Each TCR Hemichain in Generating Functional Chain-Centric TCR

Emerging Concepts in TCR Specificity: Rationalizing and (Maybe) Predicting Outcomes

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