Reversed T Cell Receptor Docking on a Major Histocompatibility Class I Complex Limits Involvement in the Immune Response

Gras, Stéphanie; Chadderton, Jesseka; Campo, Claudia M. Del; Farenc, Carine; Wiede, Florian; Josephs, Tracy M.; Sng, Xavier Y.X.; Mirams, Michiko; Watson, Katherine A.; Tiganis, Tony; Quinn, Kylie M.; Rossjohn, Jamie; Gruta, Nicole L. La

doi:10.1016/j.immuni.2016.09.007

Cited by 83 publications

(85 citation statements)

References 47 publications

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“…S2). The nondistinctive geometry is particularly clear when it is considered alongside TCRs that bind with "reverse polarity" (26,27) and the nonsignaling 42F3 TCR in complex with the p3A1 ligand (28). As a further demonstration of its traditional binding geometry, the binding of HCV1046 to NS3/A2 was not distinctive when the position of the center of mass of the Vα/Vβ domains over A2 was compared with other A2-binding receptors (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Alloreactive TCRs such as HCV1406 that bind in standard geometries could underscore a need to form a competent TCR-pMHC signaling complex that is structurally compatible with the binding of coreceptor and/or CD3 signaling units (42). There is evidence that such structural requirements do exist: In one instance, a TCR-pMHC complex with a highly unusual geometry did not signal (28), and, more recently, TCRs that bind with reverse polarity have been shown to lead to poor T-cell activation (26). On the other hand, MHC restriction has been proposed to emerge from an intrinsic bias of TCRs toward MHC proteins (43), and there is evidence that TCR genes have coevolved with genes of the MHC (44).…”

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: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Wang

Singh

Spear

et al. 2017

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

View full text Add to dashboard Cite

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“…However, the inconsistencies between the magnitude of cytokine release and/or the requirements for recognition given known affinities suggest that the population of engaged receptor is not solely dictating T-cell functional responses. Observing architectural changes in TCR-pMHC complexes may provide an answer to this dichotomy, with recent findings illustrating how altered TCR binding geometries can impact T-cell function [45,59]. …”

Section: Discussionmentioning

confidence: 99%

Critical biological parameters modulate affinity as a determinant of function in T-cell receptor gene-modified T-cells

Spear

Wang

Foley

et al. 2017

Cancer Immunol Immunother

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T cell receptor (TCR)-pMHC affinity has been generally accepted to be the most important factor dictating antigen recognition in gene-modified T-cells. As such, there is great interest in optimizing TCR-based immunotherapies by enhancing TCR affinity to augment the therapeutic benefit of TCR gene-modified T-cells in cancer patients. However, recent clinical trials using affinity-enhanced TCRs in adoptive cell transfer (ACT) have observed unintended and serious adverse events, including death, attributed to unpredicted off-tumor or off-target cross-reactivity. It is critical to re-evaluate the importance of other biophysical, structural, or cellular factors that drive the reactivity of TCR gene-modified T-cells. Using a model for altered antigen recognition, we determined how TCR-pMHC affinity influenced the reactivity of hepatitis C virus (HCV) TCR gene-modified T-cells against a panel of naturally occurring HCV peptides and HCV-expressing tumor targets. The impact of other factors, such as TCR-pMHC stabilization and signaling contributions by the CD8 co-receptor, as well as antigen and TCR density were also evaluated. We found that changes in TCR-pMHC affinity did not always predict or dictate IFNγ release or degranulation by TCR gene-modified T-cells, suggesting that less emphasis might need to be placed on TCR-pMHC affinity as a means of predicting or augmenting the therapeutic potential of TCR gene-modified T-cells used in ACT. A more complete understanding of antigen recognition by gene-modified T-cells and a more rational approach to improve the design and implementation of novel TCR-based immunotherapies is necessary to enhance efficacy and maximize safety in patients.

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“…One complexity receiving current attention is the supramolecular architecture of the TCR signaling complex. Unusual TCR binding topologies have been associated with altered immunological outcomes (17, 18), potentially by hindering coreceptor or CD3 engagement and possibly the formation of higher order clusters (6, 19, 20). Supramolecular architectural differences can in principle occur independently of TCR affinity for peptide/MHC (pMHC).…”

Section: Caution Ahead: Tcr Specificity Necessarily Invokes Binding Amentioning

confidence: 99%

“…A variety of angles make up the TCR “diagonal binding mode,” and TCRs that bind with reversed binding modes have now been described (17, 26). There are biological implications for the trends and their exceptions – for example, as noted above, TCRs that bind pMHC with outlier geometries seem to signal weaker or not at all, possibly due to supramolecular architectural limits (17, 18). A key lesson is that many of our simplifying assumptions about the rules and roles in TCR binding have turned out to be limiting.…”

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

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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Reversed T Cell Receptor Docking on a Major Histocompatibility Class I Complex Limits Involvement in the Immune Response

Abstract: 3

Cited by 83 publications

References 47 publications

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

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

Critical biological parameters modulate affinity as a determinant of function in T-cell receptor gene-modified T-cells

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

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