Structural interplay between germline interactions and adaptive recognition determines the bandwidth of TCR-peptide-MHC cross-reactivity

Adams, Jarrett; Narayanan, Samanthi; Birnbaum, Michael E.; Sidhu, Sachdev S.; Blevins, Sydney J.; Gee, Marvin H.; Sibener, Leah V.; Baker, Brian M.; Kranz, David M.; García, K. Christopher

doi:10.1038/ni.3310

Cited by 104 publications

(126 citation statements)

References 53 publications

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“…First, the dose-response seemed to exhibit a bell shape with reduced cytokine production at high pMHC concentrations. This bell shape was less pronounced or absent for low-affinity ligands, which is consistent with published studies reporting a sigmoidal dose-response for low-affinity ligands (14,15,17,18,21,23,41). Second, the peak amplitude of the bell-shaped dose-response was similar for pMHCs despite large differences in their affinities.…”

Section: T-cell Activation In Response To a 1 Million-fold Variation supporting

confidence: 80%

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

Lever

Lim

Krüger

et al. 2016

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

141

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T cells must respond differently to antigens of varying affinity presented at different doses. Previous attempts to map peptide MHC (pMHC) affinity onto T-cell responses have produced inconsistent patterns of responses, preventing formulations of canonical models of T-cell signaling. Here, a systematic analysis of T-cell responses to 1 million-fold variations in both pMHC affinity and dose produced bell-shaped dose–response curves and different optimal pMHC affinities at different pMHC doses. Using sequential model rejection/identification algorithms, we identified a unique, minimal model of cellular signaling incorporating kinetic proofreading with limited signaling coupled to an incoherent feed-forward loop (KPL-IFF) that reproduces these observations. We show that the KPL-IFF model correctly predicts the T-cell response to antigen copresentation. Our work offers a general approach for studying cellular signaling that does not require full details of biochemical pathways.

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Section: T-cell Activation In Response To a 1 Million-fold Variation supporting

confidence: 80%

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

Lever

Lim

Krüger

et al. 2016

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

141

View full text Add to dashboard Cite

show abstract

“…7b). This outcome is consistent with recent findings on TCR specificity, which suggest the existence of peptide 'hotspots' of reduced structural and chemical diversity, outside of which greater variation is permitted (Adams et al, 2016).…”

Section: Computational Scanning Of Peptide Variantssupporting

confidence: 81%

“…This allowed for successful design of new, affinity-enhancing mutations in multiple TCRs, including an unrelated receptor not used in training. The new design framework was also successful in recapitulating positive and negative effects of mutations to the MHC protein as well as substitutions in the peptide, and captured emerging themes in TCR specificity (Adams et al, 2016). Although there are avenues for improvement, these new developments greatly extend the applicability of structure-guided design for the manipulation and screening of TCR binding properties, and suggest ways for computational screening for peptide antigenicity.…”

Section: Introductionmentioning

confidence: 99%

A generalized framework for computational design and mutational scanning of T-cell receptor binding interfaces

Riley¹,

Ayres²,

Hellman³

et al. 2016

Protein Engineering, Design and Selection

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T-cell receptors (TCRs) have emerged as a new class of therapeutics, most prominently for cancer where they are the key components of new cellular therapies as well as soluble biologics. Many studies have generated high affinity TCRs in order to enhance sensitivity. Recent outcomes, however, have suggested that fine manipulation of TCR binding, with an emphasis on specificity may be more valuable than large affinity increments. Structure-guided design is ideally suited for this role, and here we studied the generality of structure-guided design as applied to TCRs. We found that a previous approach, which successfully optimized the binding of a therapeutic TCR, had poor accuracy when applied to a broader set of TCR interfaces. We thus sought to develop a more general purpose TCR design framework. After assembling a large dataset of experimental data spanning multiple interfaces, we trained a new scoring function that accounted for unique features of each interface. Together with other improvements, such as explicit inclusion of molecular flexibility, this permitted the design new affinity-enhancing mutations in multiple TCRs, including those not used in training. Our approach also captured the impacts of mutations and substitutions in the peptide/MHC ligand, and recapitulated recent findings regarding TCR specificity, indicating utility in more general mutational scanning of TCR-pMHC interfaces.

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“…Third, where the peptides are most different (p1 Lys in NS3 and p1 Glu in MART-1) is the exact region where substitutions have the greatest impact and direct cross-recognition. HCV1406 cross-reactivity with a modified MART-1 peptide therefore underscores the importance of hot spots in TCR specificity: The TCR engages a key region of the peptide that most directly influences specificity, restricting amino acid composition there but leaving other regions open to more diversity (45,46). Our observations illustrate how hotspots can work alongside mimicry in directing TCR specificity/ cross-reactivity and reinforce how peptide features working alongside the distinctive surface chemistry of allo-MHC can drive allospecificity.…”

Section: Discussionmentioning

confidence: 64%

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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Structural interplay between germline interactions and adaptive recognition determines the bandwidth of TCR-peptide-MHC cross-reactivity

Cited by 104 publications

References 53 publications

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

A generalized framework for computational design and mutational scanning of T-cell receptor binding interfaces

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

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